The role of cytokines in skin aging

DCLI A 802303 indd CLIMACTERIC 2013;16 1–8 REVIEW Received 30 01 2013 © 2013 International Menopause Society Revised 24 04 2013 DOI 10 310913697137 2013 802303 Accepted 01 05 2013 Correspondence Dr J.

CLIMACTERIC 2013;16:1–8 The role of cytokines in skin aging M Borg*, S Brincat*, G Camilleri*, P Schembri-Wismayer*, M Brincat† and J Calleja-Agius*,† *Department of Anatomy, Faculty of Medicine and Surgery, University of Malta; †Department of Obstetrics and Gynaecology, Mater Dei Hospital, Malta Key words: CUTANEOUS AGING, MENOPAUSE, CYTOKINES, TNF-α, COLLAGEN, INTERLEUKINS, INTERFERONS Climacteric Downloaded from informahealthcare.com by Linkopings University on 08/02/13 For personal use only ABSTRACT Cutaneous aging is one of the major noticeable menopausal complications that most women want to fight in their quest for an eternally youthful skin appearance It may contribute to some maladies that occur in aging which, despite not being life-threatening, affect the well-being, psychological state and quality of life of aged women Skin aging is mainly affected by three factors: chronological aging, decreased levels of estrogen after menopause, and environmental factors Aged skin is characterized by a decrease in collagen content and skin thickness which result in dry, wrinkled skin that is easily bruised and takes a longer time to heal Cytokines play a crucial role in the manifestation of these features of old skin The pro-inflammatory cytokine tumor necrosis factor-alpha inhibits collagen synthesis and enhances collagen degradation by increasing the production of MMP-9 It also lowers the skin immunity and thus increases the risk of cutaneous infections in old age Deranged levels of several interleukins and interferons also affect the aging process The high level of CCN1 protein in aged skin gives dermal fibroblasts an ‘age-associated secretory phenotype’ that causes abnormal homeostasis of skin collagen and leads to the loss of the function and integrity of skin Further research is required especially to establish the role of cytokines in the treatment of cutaneous aging INTRODUCTION It is estimated that within the next 50 years, one-third of all women will be in their menopausal phase1 Although many people consider skin aging as an inevitable part of the aging process, wrinkled and sagging skin is a disease which can be fought2 Several studies suggest that the imbalanced levels of various cytokines, such as interleukins and tumor necrosis factor-alpha (TNF-α), during menopause contribute to the menopausal complications3 The role of cytokines in osteoporosis and cardiovascular disease in menopause has been well studied3–5; however, their role in skin aging still needs to be explored further SKIN AGING Three important factors affect skin aging These are the natural process of aging (known as chronological aging)6, decreased estrogen levels (which typically happen in women after menopause)7, and harmful environmental factors like ultraviolet (UV) radiation8 and smoking9 There are two major processes through which skin ages – the intrinsic and extrinsic processes Intrinsic aging varies among individuals and depends on their genetic make-up8 This type of aging cannot be avoided In contrast, extrinsic skin aging can be modulated and depends on the individual’s lifestyle Extrinsic cutaneous aging is a type of premature skin aging It occurs by exposing the skin to harmful environmental factors such as poor nutrition, smoking, the sun and large alcohol intake8 CHANGES IN THE SKIN AFTER MENOPAUSE Skin which has undergone intrinsic aging sometimes looks nearly as smooth and flawless as normal skin except for a few exaggerated expression lines8 However, several changes occur to the skin after menopause and the appearance of skin may change quite significantly With the onset of menopause, the skin becomes dry because the functions of the sebaceous glands and sweat glands decline and with time they become unresponsive to stimuli This is associated with decreased estrogen levels10 Correspondence: Dr J Calleja-Agius, Department of Obstetrics and Gynaecology, Mater Dei Hospital, B’Kara, Malta REVIEW © 2013 International Menopause Society DOI: 10.3109/13697137.2013.802303 Received 30-01-2013 Revised 24-04-2013 Accepted 01-05-2013 Climacteric Downloaded from informahealthcare.com by Linkopings University on 08/02/13 For personal use only The role of cytokines in skin aging Menopause brings with it changes in collagen type, quality, amount, metabolism and turnover11 The skin becomes rapidly thinner after menopause at a rate similar to the decrease in bone mass10 The reduction in thickness cannot be attributed to age alone10 The thickness of the skin decreases by 1.13% every year in the initial postmenopausal period12, while the collagen content decreases by 2.1% every postmenopausal year13 The decline in skin collagen and skin thickness is reflected in dry, flaky, wrinkled and easily bruised skin11 The postmenopausal period is marked by low amounts of soluble collagen, a slower turnover and collagen synthesis This manifests itself in decreased skin resilience and pliability14 It is the decrease in collagen content and change in skin elasticity that contribute to the appearance of old skin15 There are both estrogen and androgen receptors in skin fibroblasts10,16 Skin is rich in estrogen receptors and estrogens bind actively and are metabolized by the skin14 Menopause brings with it a decrease in the density of hair follicles in the scalp and body14 Changes in estrogen levels with the onset of menopause alter the skin vascularization17 and the connective tissue in the dermis11 Changes in the dermal connective tissue occur as a result of increased hydroxyproline turnover and mucopolysaccharide incorporation11 When estrogen therapy is administered for weeks, the number of capillaries increases, atrophy of the epidermis disappears, and collagen fibers appear less fragmented18 Both estriol succinate and estradiol valerate have been shown to thicken the epidermis of castrated women after months from the start of treatment19 As a result of intrinsic aging, the epidermis and dermis atrophy, the amount of fibroblasts decreases and the epidermal rete ridges become flat20 There is an increase in the ratio of type III to type I collagen8,21 Aging brings with it a decline in procollagen types I and III mRNA and protein expression22 As well as the impairment in collagen synthesis, an increase in the production of various matrix metalloproteinases (MMPs) also occurs with aging, especially of MMP-1, MMP-2, MMP-3, and MMP-922,23 The production of all of these MMPs except gelatinase A (MMP-2) is governed by activator protein-1 (AP-1)22 AP-1 is a transcription factor that inhibits the expression of procollagen gene in fibroblasts as well as stimulating MMP gene transcription in both fibroblasts and keratinocytes24 The expression of AP-1 is higher than normal in aged fibroblasts taken from skin samples in vitro22,25 and also higher than in younger skin in vivo22,23 Oxidative damage to cells accumulates with years and the free radicals and reactive oxygen species (ROS) from aerobic metabolism initiate the aging process26 Furthermore, the anti-oxidant defenses decline with aging27 The increased ROS participate in various mitogen-activated protein (MAP) kinase pathways that activate mitogen-activated protein kinase (MAPK) MAPK induces AP-1 which consequently increases the expression of MMPs These mechanisms are responsible for the decreased amount of collagen in old skin22 The main theory that is believed to contribute to the aging process of skin is the accumulation of ROS26 This oxidative Borg et al stress occurring in cells damages the DNA, causing mutations, and oxidizes proteins which then lose their function Furthermore, it oxidizes lipids found in membranes which lose their transport capacity and have distorted transmembrane signalling24 THE MICRO-INFLAMMATORY MODEL OF SKIN AGING External stimuli such as cigarette smoke and UV radiation, together with internal stimuli like hormone changes that accompany menopause, trigger the production of adhesion molecules, which are responsible for the first step in the inflammatory process28 External stimuli also induce nerve endings to release various neuropeptides into the skin29 These neuropeptides increase the synthesis of adhesion molecules Adhesion molecules enable circulating monocytes and granulocytes to roll over, adhere and diapedese through the endothelial wall of blood vessels and migrate into the dermis28 These white blood cells produce and secrete proteases and ROS that in turn change the turnover of the proteins of the dermis and also damage cells in the skin The damaged cells are stimulated to release leukotrienes and prostaglandins28 These chemicals act as stimuli on the mast cells and induce the secretion of histamine and the cytokine TNF-α, which in turn stimulate endothelial cells to produce intracellular adhesion molecule-1 (ICAM-1) and also help liberate P-selectins28 A second set of immune cells is stimulated to migrate, causing more inflammation, and the process goes on and on The final result would be an imbalance in the degradation and synthesis of elastin and collagen fibers Since the fibroblasts in old age are unable to synthesize these fibers in oriented arrays, this inflammatory process causes aging of the skin with a change in the composition of the dermis and epidermis, skin thickness and elastic properties of the skin28 CYTOKINES Cytokines play an important role in skin aging These cellsignalling proteins serve as an intercellular communication link They are produced by cells of the immune system such as Langerhans cells and other cells in the skin, including keratinocytes and epithelial cells30 Several cytokines that act on the skin target cells have pleiotropic and redundant effects30 This is due to similarities in their amino acid sequence which enable some cytokines, especially the interleukins, to bind to the same cell receptors Usually, receptors have a very high affinity to the cytokines; therefore, the concentration of cytokines in the body would be low, typically femtomolar or nanomolar However, this concentration increases with trauma or infection The action of cytokines is usually brought about in a cascade involving several cytokines acting simultaneously or after each other Their action is brought to an end by other inhibitory cytokines or by the receptors themselves31 Climacteric The role of cytokines in skin aging Climacteric Downloaded from informahealthcare.com by Linkopings University on 08/02/13 For personal use only TNF-a AND SKIN AGING In the skin, TNF-α is produced by fibroblasts32, macrophages, monocytes and keratinocytes30 TNF-α is initially membranebound but it is then cleaved by TNF-α-converting enzyme to a soluble protein These two forms of TNF-α are both biologically active on forming non-covalently linked homotrimers33 TNF-α brings about its effects by binding to the receptors TNFR1 or TNFR2 which are both located on cell membranes33 Ultraviolet B (UVB) radiation promotes the production of TNF-α by dermal fibroblasts and epidermal keratinocytes and this increases inflammation34 Macrophages that reside in the skin secrete TNF-α35, a cytokine which triggers inflammatory responses36 However, macrophages in the skin of old people secrete only a very small amount of TNF-α This decrease in cutaneous macrophage TNF-α secretion with age results in defective activation of the blood vessels of the dermis and hence a decreased recruitment of antigen-specific CD4 ϩ T cells from the blood to areas of the skin where antigens would have entered35 This leads to an increased occurrence of cutaneous infections37 while immunity decreases with age38 This is, in fact, shown by decreased skin delayed-type hypersensitivity (DTH) responses to previously sensitized antigens35 The DTH response of old skin to particular recall antigens introduced via intradermal injections was investigated35 Antigens used were the bacterium tuberculin purified protein derivative, varicella zoster virus and Candida albicans (fungus) For all the three different types of microorganisms, skin biopsy samples showed low TNF-α levels and DTH response The macrophages were studied to determine the cause of the low TNF-α When Toll-like receptor (TLR) ligands were added, the macrophages secreted a considerable amount of TNF-α This showed that the macrophages residing in old skin are not defective but are inactivated CD4 ϩ Foxp3 ϩ regulatory T cells, which are present in large amounts in the skin of elderly people, inhibit macrophages from secreting TNF-α35,39 These T regulatory cells inhibit the process of macrophage activation and the secretion of TNF-α40 The DTH response of the skin studied in vitro manifests the responsiveness of memory T cells in vivo As the skin reactivity to antigens decreases with aging, old people are more susceptible to skin infections and malignancy37 TNF-α stimulates the expression of adhesion molecules on endothelial cells, mainly E-selectin, ICAM-1, and VCAM-1, and hence helps leukocytes to migrate through the blood vessels into the dermis35 When anti-TNF-α is given as a treatment for rheumatoid arthritis, patients often suffer from skin infections due to the decreased leukocyte migration41 In elderly people, the function of TLR1 and TLR2 on cutaneous macrophages may be defective after they bind to their ligands42 This defect may be responsible for the decreased secretion of TNF-α by macrophages when the recall antigen C albicans was used to infect skin, as this species binds to TLR1 and TLR235 A defect with TLR4 expression and function of macrophages in old skin was also Climacteric Borg et al observed by other investigators43–45 although not shown by others46 When these three receptors were stimulated in vitro, cutaneous macrophages and monocytes from peripheral blood secreted TNF-α and this confirmed that the defect was reversible35 Besides signals from TLRs to become activated, macrophages need cytokines like interferon gamma (IFN-γ) in order to achieve their maximum functional capacity35 However, skin samples lacked this cytokine35 and this could be the reason for the low amount of T cells that migrated to the site of antigen challenge IFN-γ is required for the expression of some genes of the macrophage, including the MHC class II genes The expression of MHC class II by the macrophage is necessary for antigen presentation to the T cells47 If this does not happen (as occurs in old people), the immune response cannot occur due to a block in the cascade35 With old age, the decrease in macrophage activation leads to reduced memory T-cell immunosurveillence and chronic non-specific inflammatory responses35 This results in an accumulation of debris in skin tissue and blood vessels which can act as a predisposing factor for infection and malignancy in aged skin and other complications like crystal arthritis and macular degeneration due to lipofuscin pigment accumulation35,48 With menopause, levels of the cytokine TNF-α in the circulation are elevated3,49,50 At high concentrations, TNF-α increases the synthesis of collagenase as well as inhibiting collagen synthesis51 TNF-α has a key role in inflammatory responses that occur in the skin It is able to modulate the expression of the MMP gene and is responsible for inducing the production of MMP-9, an enzyme that causes skin aging by causing skin damage and does not allow its repair52 When the cells of the epidermis are exposed to persistent TNF-α, the production of MMP-9 is disturbed and the epidermis can be damaged irreversibly52 Inflammatory signals upregulate MMP-953 The transcription of MMP genes is regulated by the transcription factors AP-154 and nuclear factor kappa B (NF-κB)52 TNF-α increases the binding activity of these transcription factors to the MMP-9 DNA sequence and hence increases the production of MMP-9 protein52 The effect of 3-deoxysappanchalcone, a flavonoid having anti-inflammatory and antioxidant properties55, was investigated in combination with MMP-952 The 3-deoxysappanchalcone decreased inflammation by reducing the expression of MMP-952 3-Deoxysappanchalcone also has anti-allergic properties56, is able to cause apoptosis57, and works against the influenza virus58 The 3-deoxysappanchalcone inhibited the DNA binding activity of AP-152 The higher the concentration of 3-deoxysappanchalcone used, the larger the reduction in the expression and activity of AP-1 protein which decreased the expression of MMP-9 protein52 The 3-deoxysappanchalcone also inhibited directly TNF-α-induced NF-κB52 Further investigations were carried out to determine which part of the translocation process of NF-κB 3-deoxysappanchalcone The role of cytokines in skin aging affected Western blot showed that the degradation and phosphorylation of IκBa, a protein that inhibits NF-κB, was not affected by this anti-inflammatory agent This suggests that 3-deoxysappanchalcone directly inhibited the activity of NF-κB52 3-Deoxysappanchalcone can inhibit the expression of MMP-9 at both the mRNA and protein levels in human keratinocytes by blocking the activation of both AP-1 and NF-κB transcription factors52 Cosmetic and pharmacological products that inhibit the transcription factors of MMP-9 can help skin renewal52 Climacteric Downloaded from informahealthcare.com by Linkopings University on 08/02/13 For personal use only TNF-a AND THE CELL CYCLE OF KERATINOCYTES TNF-α may help the skin to remove damaged cells and mediates UVB-induced apoptosis When pre-malignant keratinocytes are irradiated with UVB, their TNF-α secretion in the epidermis increases rapidly This increased TNF-α eliminates the G2/M checkpoint of the cell cycle of keratinocytes and inhibits the repair of damaged DNA although it increases apoptosis33 The cells escape this checkpoint and accumulate mutations, leading to the development of tumors TNF-α activates protein kinase B (Akt) and regulates the transcription factor FoxO3a, the pro-apoptotic protein Bad, the protein kinase mTOR and the atypical protein kinase C (aPKC) The reduction in the repair of damaged DNA is caused by the aPKC–Akt axis However, when these keratinocytes were treated with infliximab (an anti-TNF-α monoclonal antibody) therapy, DNA repair was inhibited despite the enhancement of the G2/M cell cycle checkpoint and apoptosis33 TNF-α mediates skin aging by inhibiting collagen synthesis and by increasing the production of MMP-9 which causes collagen degradation51,52 The decrease in cutaneous macrophage TNF-α secretion with age decreases the skin immunity, with a resultant increase in cutaneous infections in old skin37,38 INTERLEUKIN-1 Active interleukin-1 (IL-1) is found in the stratum corneum of the epidermis59 The stratum corneum is the outermost layer of the epidermis and it is mostly composed of dead cells60,61 IL-1α and interleukin-1 receptor antagonist (IL-1ra) are both produced by keratinocytes in the skin IL-1ra operates through competitive inhibition by binding to the common receptors on several target cells59 although other investigators suggest that it only binds to IL-1 receptor type I62 Several stimuli such as UVB radiation stimulate keratinocytes in the epidermis to release IL-1α which induces cytokines and adhesion molecules to bring about skin inflammation In turn, IL-1ra inhibits the activities of IL-1α and the balance between these two cytokines helps preserve homeostasis of the skin59 Borg et al The effect of aging and gender (and hence also menopause indirectly) on the content of IL-1α and IL-1ra in the stratum corneum has been investigated59 The variables of skin exposed to UVB (the face) and skin not exposed (inside of upper arm) were also taken into account The IL-1 levels measured in the facial skin layer did not change significantly with age However, in the layer of the inside of the upper arm, IL-1α levels were higher in aged skin while IL-1ra decreased with age There was no difference between the genders and hence menopause does not alter the concentration of IL-1 cytokines in the stratum corneum59 However, other researchers have reported an increase in the expression of IL-1ra in cultured human keratinocytes with aging, while the expression decreased in photo-aged skin keratinocytes63 INTERLEUKIN-18 IL-18, formerly known as interferon-gamma inducing factor is an immunoregulatory cytokine produced by epithelial cells, dendritic cells and macrophages It is a proinflammatory cytokine that increases the expression of cell adhesion molecules, contributes to atherosclerosis and brings about the aging process62 Therapeutic strategies aimed at reducing the level of IL-18 may slow the aging process62 IL-18 also plays a role in type T-helper cell polarization When it is overexpressed, it worsens both allergic and nonallergic skin inflammation64 It is also involved in autoimmune diseases62 However, IL-18 protects against skin damage caused from exposure to UVB radiation and hence decreases UVinduced apoptosis65 It also helps prevent UV-induced immunosuppression65 INTERLEUKIN-6 IL-6 functions as a pro-inflammatory and an antiinflammatory cytokine via different signalling mechanisms66 It participates in various inflammatory and immune responses67 IL-6 synthesis is induced by transforming growth factor-alpha (TGF-α) in human keratinocytes68 IL-6 in turn helps the keratinocytes to proliferate69 However, other investigators have not found an increase in keratinocyte proliferation with keratinocyte-directed IL-6 expression in transgenic mice67 IL-6 expression in transgenic mice causes the stratum corneum to become thicker; however, it does not enhance epidermal proliferation or cause leukocyte infiltration, suggesting that IL-6 does not have a direct proinflammatory activity in the skin despite being elevated in inflammatory diseases like rheumatoid arthritis67 The decline in estrogen level that occurs in menopause is accompanied by an increase in IL-6 production3 However, this increase is very small when compared to the elevated levels that occur in infection or tissue injury70 Skin keratinocytes are stimulated to increase the production of IL-6 after exposure to TNF-α, IFN-γ or IL-471 IL-6 is Climacteric The role of cytokines in skin aging involved in the aging of skin and in the formation of skin wrinkles IL-6 levels are further upregulated on exposure to ultraviolet radiation72 Climacteric Downloaded from informahealthcare.com by Linkopings University on 08/02/13 For personal use only INTERFERONS Interferons have several antiproliferative and antiviral activities Fibroblasts, the major type of cells in the dermis, undergo senescence after exposure to interferon beta (IFN-β) through a DNA damage signalling pathway73 Fibroblasts produce collagen, mainly types I and III18 On the other hand, continuous exposure to IFN-α decreases population doublings of dermal microvascular endothelial cells and induces their senescent phenotype74 IFN-γ belongs to the macrophage-activating factor family of cytokines It is produced by T lymphocytes, including those that home in the skin and have the cutaneous lymphocyte antigen (CLA) It participates in both adaptive and innate immunity There seems to be no change in the number of IFN-γ-producing CLAϩ T cells in old age75 T-lymphocyte-dependent immune reactions are stimulated by CD1aϩ (Langerhans) cells Evidence shows that these cells decrease linearly with age and, as a consequence, aged skin has decreased immunosurveillance Studies on the effect of IFN-α on Langerhans cells on biopsies of preauricular skin showed that, after application of alpha-interferon cream, the skin samples taken from the group aged between 57 and 75 years had increased numbers of cutaneous CD1aϩ cells76 EFFECT OF CCN ON THE SKIN CONNECTIVE TISSUE The connective tissue of the skin consists primarily of collagen that is produced by fibroblasts located in the dermal layer of the skin These fibroblasts are also responsible for the degradation of collagen in the extracellular matrix With old age, dermal fibroblasts express an ‘age-associated secretory phenotype’ which is believed to be caused by a high level of cysteinerich protein 61 (CCN1) in aged skin77 The end result is an abnormal homeostasis of skin collagen type I whose degradation is upregulated and its production reduced78 CCN1 or CRY61 belongs to the protein family of CCNs, a family made up of six matricellular proteins that inter-relate with the extracellular matrix77,79 This protein changes the way some cytokines work, for example it causes TNF-α to express cytotoxic properties without inhibiting NF-κB activity It also supports the adhesion of murine macrophages and enhances the expression of a pro-inflammatory genetic profile that is typical of activated M1 macrophages that take part in T1 helper cell responses Furthermore, CCN1 increases the levels of the cytokines IL-1α, IL-1β, IL-6, IL-12b, and TNF-α while it downregulates the expression of anti-inflammatory factor TGF-β80 This change in genetic profile is regulated via two mechanisms, either by a direct activation of NF-κB by Climacteric Borg et al CCN1, known as the immediate-early response, or by a delayed response that is brought about through CCN1induced TNF-α80 CCN1 elevates the amount of ROS in the cell by interacting with integrins81 The high level of ROS activates NF-κB and MAPK signalling which then upregulate the production of IL-1β and IL-682 The expression of MMPs in aged dermal fibroblasts is increased by the cytokines IL-1β and IL-6, which also decrease the production of collagen, further imbalancing collagen homeostasis82,83 IL-1β reduces the TGF-β type II receptor and hence impairs TGF-β signalling in aged dermal fibroblasts, causing aberrant collagen homeostasis78 The secretory phenotype of dermal fibroblasts in old age results in aging of the skin connective tissue and brings about the loss of function and integrity of old skin77 CONCLUSION Cutaneous aging is one of the major noticeable menopausal complications that most women want to fight in their quest for an eternally youthful skin appearance Skin aging is not a uniform biological event and varies between individuals84 It is mainly affected by three factors: chronological aging6, decreased levels of estrogen after menopause7, and environmental factors8 Aged skin is characterized by a decrease in collagen content and skin thickness, which result in dry, wrinkled skin that is easily bruised and takes a long time to heal84 Cytokines play a central role in the manifestation of these features of old skin TNF-α inhibits collagen synthesis and enhances collagen degradation by increasing the production of MMP-951,52 It also lowers the skin immunity and thus increases the risk of cutaneous infections in old age37,38 IL-1α and IL-18 levels are higher in aged skin and promote skin inflammation, while IL-1ra decreases with age59 IL-18 also contributes to atherosclerosis62 The level of IL-6 is slightly increased after menopause and this helps keratinocyte proliferation69 and increases the stratum corneum thickness in transgenic mice67 The amount of IFN-γ-producing CLAϩ T cells is not altered in old skin IFN-γ participates in both adaptive and innate immunity75 On the other hand, application of alpha-interferon cream on aged skin increases the number of cutaneous Langerhans cells that are responsible for skin immunosurveillance76 Aged skin expresses a high level of CCN1 protein which gives dermal fibroblasts an ‘ageassociated secretory phenotype’, resulting in an abnormal homeostasis of skin collagen and causing old skin to lose its function and integrity77,78 Further research is required especially to establish the role of cytokines in the treatment of cutaneous aging Conflict of interest The authors report no confl ict of interest The authors alone are responsible for the content and writing of this paper Source of funding Nil The role of cytokines in skin aging Borg et al Climacteric Downloaded from informahealthcare.com by Linkopings University on 08/02/13 For personal use only References Puizina-Ivic´ N Skin aging Acta Dermatovenerol Alp Panonica Adriat 2008; 17:47–54 Perricone N The Wrinkle Cure New York: Warner Books, 2001:207 Pfeilschifter J, Koditz R, Pfohl M, Schatz H Changes in proinflammatory cytokine activity after menopause Endocr Rev 2002;23:90–199 Vitale C, Cornoldi A, Gebara O, et al Interleukin-6 and flow mediated dilatation as markers of increased vascular inflammation in women receiving hormone therapy Menopause 2005;12: 552–8 Zupan J, Komadina R, Marc J The relationship between osteoclastogenic and anti-osteoclastogenic pro-inflammatory cytokines differs in human osteoporotic and osteoarthritic bone tissues J Biomed Sci 2012;19:28 Sugimoto M, Yamashita R, Ueda M Telomere length of the skin in association with chronological aging and photoaging J Dermatol Sci 2006;43:43–7 Raine-Fenning N, Brincat M, Muscat-Baron Y Skin aging and menopause implications for treatment Am J Clin Dermatol 2003;4:371–8 Baumann L Skin ageing and its treatment J Pathol 2007;211: 241–51 Martires KJ, Fu P, Polster AM, Cooper KD, Baron ED Factors that affect skin aging: a cohort-based survey on twins Arch Dermatol 2009;145:1375–9 10 Brincat M, Muscat-Baron Y, Galea R The menopause In Shaw RW, Soutter WP, Stanton SL, eds Gynaecology London: Churchill Livingstone, 1997:373–92 11 Brincat MP, Galea R Estrogens and skin In Studd J, ed The Management of the Menopause Annual Review 1998 Lancaster, UK: Parthenon Publishing Group Ltd, 1998:19–25 12 Brincat M, Moniz CF, Kabalan S, et al Decline in skin collagen content and metacarpal index after the menopause and its prevention with sex hormone replacement Br J Obstet Gynaecol 1987;94:126–9 13 Brincat M, Versi E, Moniz CF, Magos A, de Trafford J, Studd JW Skin collagen changes in post-menopausal women receiving different regimens of estrogen therapy Obstet Gynecol 1987; 70:123–7 14 Utian WH The menopause and climacteric In Philipp E, Setchell M, Ginsburg J, eds Scientific Foundations of Obstetrics and Gynaecology, 4th edn Oxford: Butterworth-Heinemann Ltd, 1991:199–207 15 Brincat M, Moniz CF, Studd JW, Darby AJ, Magos A, Cooper D Sex hormones and skin collagen content in postmenopausal women Br Med J 1983;287:1337–8 16 Black MM, Shuster S, Bottoms E Osteoporosis, skin collagen, and androgen BMJ 1970;4:773–4 17 Goodrich SM, Wood JE The effect of oestradiol 17β on peripheral venous distensibility and velocity of venous blood flow Am J Obstet Gynecol 1966;96:407–12 18 Brincat M, Studd J Skin and the menopause In Studd J, Whitehead MI, eds The Menopause London: Blackwell Scientific Publications, 1988:85–101 19 Punnonen R Effect of castration and peroral therapy on skin Acta Obstet Gynaecol Scand 1973;21:S1–44 20 Roupe G Skin of the aging human being Lakartidningen 2001;98:1091–5 21 Lovell CR, Smolenski KA, Duance VC, Light ND, Young S, Dyson M Type I and III collagen content and fibre distribution 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 in normal human skin during ageing Br J Dermatol 1987;117: 419–28 Rittié L, Fisher GJ UV-light-induced signal cascades and skin aging Ageing Res Rev 2002;1:705–20 Chung JH, Kang S, Varani J, Lin J, Fisher GJ, Voorhees JJ Decreased extracellular-signal-regulated kinase and increased stress-activated MAP kinase activities in aged human skin in vivo J Invest Dermatol 2000;115:177–82 Fisher GJ, Kang S, Varani F, et al Mechanisms of photoaging and chronological skin aging Arch Dermatol 2002;138: 1462–70 Chen W, Borchers AH, Dong Z, Powell MB, Bowden GT UVB irradiation-induced activator protein-1 activation correlates with increased c-fos gene expression in a human keratinocyte cell line J Biol Chem 1998;273:32176–81 Hensley K, Floyd R Reactive oxygen species and protein oxidation in aging: a look back, a look ahead Arch Biochem Biophys 2002;397:377–83 Hu HL, Forsey RJ, Blades TJ, Barratt ME, Parmar P, Powell JR Antioxidants may contribute in the fight against ageing: an in vitro model Mech Ageing Dev 2000;121:217–30 Giacomoni P, Declercq L, Hellemans L, Maes D Aging of human skin: review of a mechanistic model and first experimental data IUBMB Life 2000;49:259–63 Quinlan KL, Song IS, Bunnett NW, et al Neuropeptide regulation of human dermal microvascular endothelial cell ICAM-1 expression and function Am J Physiol 1998;275: C1580–90 Feliciani C, Gupta AK, Saucier DN Keratinocytes and cytokine/ growth factors Crit Rev Oral Biol Med 1996;7:300–18 Calleja-Agius J, Muttukrishna S, Jauniaux E The role of tumour necrosis factor alpha (TNFα) in human female reproduction Expert Rev Endocrinol Metab 2009;4:273–82 Bashir MM, Sharma MR, Werth VP TNF-alpha production in the skin Arch Dermatol Res 2009;301:87–91 Faurschou A Role of tumor necrosis factor-α in the regulation of keratinocyte cell cycle and DNA repair after ultraviolet-B radiation Dan Med Bull 2010;57:B4179 Bashir MM, Sharma MR, Werth VP UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription J Invest Dermatol 2009;129:994–1001 Agius E, Lacy KE, Vukmanovic-Stejic M, et al Decreased TNF-α synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4 ϩ T cells during aging Exp Med 2009; 206:1929–40 Dada LA, Sznajder JI Mitochondrial Ca2 ϩ and ROS take center stage to orchestrate TNF-α-mediated inflammatory responses J Clin Invest 2011;121:1683–5 Laube S Skin infections and aging Aging Res Rev 2004;3: 69–89 Yoshikawa TT Epidemiology and unique aspects of aging and infectious diseases Clin Infect Dis 2000;30:931–3 Vukmanovic-Stejic M, Zhang Y, Cook JE, et al Human CD4 ϩ CD25hi Foxp3 ϩ regulatory T cells are derived by rapid turnover of memory populations in vivo J Clin Invest 2006; 116:2423–33 Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS CD4 ϩ CD25ϩ Foxp3 ϩ regulatory T cells induce alternative activation of human monocytes/macrophages Proc Natl Acad Sci USA 2007;104:19446–51 Climacteric Climacteric Downloaded from informahealthcare.com by Linkopings University on 08/02/13 For personal use only The role of cytokines in skin aging 41 Dixon WG, Watson K, Lunt M, Hyrich K, Silman AJ, Symmons DP Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register Arthritis Rheum 2006;54:2368–76 42 van Duin D, Mohanty S, Thomas V, et al Age-associated defect in human TLR-1/2 function J Immunol 2007;178:970–5 43 Renshaw M, Rockwell J, Engleman C, Gewirtz A, Katz J, Sambhara S Cutting edge: impaired Toll-like receptor expression and function in aging J Immunol 2002;169:4697–701 44 van den Biggelaar AH, Huizinga TW, de Craen AJ, et al Impaired innate immunity predicts frailty in old age The Leiden 85-plus study Exp Gerontol 2004;39:1407–14 45 Krabbe KS, Pedersen M, Bruunsgaard H Inflammatory mediators in the elderly Exp Gerontol 2004;39:687–99 46 van Duin D, Shaw AC Toll-like receptors in older adults J Am Geriatr Soc 2007;55:1438–44 47 Cullell-Young M, Barrachina M, López-López C, et al From transcription to cell surface expression, the induction of MHC class II I-A alpha by interferon-gamma in macrophages is regulated at different levels Immunogenetics 2001;53: 136–44 48 Richards A Kavanagh D, Atkinson JP Inherited complement regulatory protein deficiency predisposes to human disease in acute injury and chronic inflammatory states the examples of vascular damage in atypical hemolytic uremic syndrome and debris accumulation in age-related macular degeneration Adv Immunol 2007;96:141–77 49 Pacifici R, Brown C, Puscheck E, et al Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells Proc Natl Acad Sci USA 1991;88:5134–8 50 Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST) Circulation 2001;103:2055–9 51 Chou DH, Lee W, McCulloch CA TNF-alpha inactivation of collagen receptors: implications for fibroblast function and fibrosis J Immunol 1996;156:4354–62 52 Youn UJ, Nam KW, Kim HS, et al 3-Deoxysappanchalcone inhibits tumor necrosis factor-α-induced matrix metalloproteinase-9 expression in human keratinocytes through activated protein-1 inhibition and nuclear factor-kappa B DNA binding activity Biol Pharm Bull 2011;34:890–3 53 Saja K, Babu MS, Karunagaran D, Sudhakaran PR Antiinflammatory effect of curcumin involves downregulation of MMP-9 in blood mononuclear cells Int Immunopharmacol 2007;7:1659–67 54 Crawford HC, Matrisian LM Mechanisms controlling the transcription of matrix metalloproteinase genes in normal and neoplastic cells Enzyme Protein 1996;49:20–37 55 Ban HS, Suzuki K, Lim SS, et al Inhibition of lipopolysaccharideinduced expression of inducible nitric oxide synthase and tumor necrosis factor-alpha by 2’-hydroxychalcone derivatives in RAW 264.7 cells Biochem Pharmacol 2004;67:1549–57 56 Yodsaoue O, Cheenpracha S, Karalai C, Ponglimanont C, Tewtrakul S Anti-allergic activity of principles from the roots and heartwood of Caesalpinia sappan on antigeninduced beta-hexosaminidase release Phytother Res 2009;23: 1028–31 57 Lee YM, Jeong GS, Lim HD, An RB, Kim YC, Kim EC Isoliquiritigenin 2′-methyl ether induces growth inhibition and apoptosis in oral cancer cells via heme oxygenase-1 Toxicol In Vitro 2010;24:776–82 Climacteric Borg et al 58 Liu AL, Shu SH, Qin HL, Lee SM, Wang YT, Du GH In vitro anti-influenza viral activities of constituents from Caesalpinia sappan Planta Med 2009;75:337–9 59 Hirao T, Aoki H, Yoshida T, Sato Y, Kamoda H Elevation of interleukin receptor antagonist in the stratum corneum of sunexposed and ultraviolet B-irradiated human skin J Invest Dermatol 1996;106:1102–7 60 Kligman AM The biology of the stratum corneum In The Epidermis New York: Academic Press, 1964:387–433 61 Kligman AM A brief history of how the dead stratum corneum became alive In Elias PM, Feingold KR, eds Skin Barrier New York: Taylor & Francis, 2006:15–24 62 Dinarello CA Interleukin and interleukin 18 as mediators of inflammation and the aging process Am J Clin Nutr 2006;83: S2447–55 63 Garmyn M, Yaar M, Boileau N, Backendorf C, Gilchrest BA Effect of aging and habitual sun exposure on the genetic response of cultured human keratinocytes to solar-simulated irradiation J Invest Dermatol 1992;99:743–8 64 Kawase Y, Hoshino T, Yokota K, et al Exacerbated and prolonged allergic and non-allergic inflammatory cutaneous reaction in mice with targeted interleukin-18 expression in the skin J Invest Dermatol 2003;121:502–9 65 Schwarz A, Maeda A, Ständer S, van Steeg H, Schwarz T IL-18 reduces ultraviolet radiation-induced DNA damage and thereby affects photoimmunosuppression J Immunol 2006;176:2896–901 66 Rose-John S IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6 Int J Biol Sci 2012;8:1237–47 67 Turksen K, Kupper T, Degenstein L, Williams I, Fuchs E Interleukin 6: insights to its function in skin by overexpression in transgenic mice Proc Natl Acad Sci USA 1992;89:5068–72 68 Aragane Y, Yamada H, Schwarz A, et al Transforming growth factor-alpha induces interleukin-6 in the human keratinocyte cell line HaCaT mainly by transcription activation J Invest Dermatol 1996;106:1192–7 69 Grossman RM, Krueger J, Yourish D, et al Interleukin is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes Proc Natl Acad Sci USA 1989;86:6367–71 70 Cohen MC, Cohen S Cytokine function: a study in biologic diversity Am J Clin Pathol 1996;105:589–98 71 Li J, Farthing PM, Ireland GW, Thornhill MH IL-1α and IL-6 production by oral and skin keratinocytes: similarities and differences in response to cytokine treatment in vitro J Oral Pathol Med 1996;25:157–62 72 Omoigui S The interleukin-6 inflammation pathway from cholesterol to aging – role of statins, bisphosphonates and plant polyphenols in aging and age-related diseases Immun Ageing 2007;4:1 73 Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation Mol Biol Cell 2006; 17:1583–92 74 Pammer J, Reinisch C, Birner P, Pogoda K, Sturzl M, Tschachler E Interferon-alpha prevents apoptosis of endothelial cells after short-term exposure but induces replicative senescence after continuous stimulation Lab Invest 2006;86:997–1007 75 Neuber K, Schmidt S, Mensch A Telomere length measurement and determination of immunosenescence-related markers (CD28, CD45RO, CD45RA, interferon-γ and interleukin-4) in skin-homing T cells expressing the cutaneous lymphocyte antigen: indication of a non-ageing T-cell subset Immunology2003;109:24–31 76 Ghersetich I, Lotti T Alpha-interferon cream restores decreased levels of Langerhans/indeterminate (CD1aϩ) cells in aged and PUVA-treated skin Skin Pharmacol 1994;7:118–20 The role of cytokines in skin aging 81 Jun JI, Lau LF The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing Nat Cell Biol 2010;12:676–85 82 Maggio M, Guralnik JM, Longo DL, Ferrucci L Interleukin-6 in aging and chronic disease: a magnificent pathway J Gerontol A Biol Sci Med Sci 2006;61:575–84 83 Baugé C, Legendre F, Leclercq S, et al Interleukin-1beta impairment of transforming growth factor beta1 signaling by down-regulation of transforming growth factor beta receptor type II and up-regulation of Smad7 in human articular chondrocytes Arthritis Rheum 2007;56:3020–32 84 Calleja-Agius J, Muscat-Baron Y, Brincat MP Skin ageing Menopause Int 2007;13:60–4 Climacteric Downloaded from informahealthcare.com by Linkopings University on 08/02/13 For personal use only 77 Quan T, Qin Z, Robichaud P, Voorhees JJ, Fisher GJ CCN1 contributes to skin connective tissue aging by inducing ageassociated secretory phenotype in human skin dermal fibroblasts J Cell Commun Signal 2011;5: 201–7 78 Quan T, He T, Shao Y, et al Elevated cysteine-rich 61 mediates aberrant collagen homeostasis in chronologically aged and photoaged human skin Am J Pathol 2006;169:482–90 79 Chen CC, Lau LF Functions and mechanisms of action of CCN matricellular proteins Int J Biochem Cell Biol 2009;41: 771–83 80 Bai T, Chen C, Lau LF Matricellular protein CCN1 activates a proinflammatory genetic program in murine macrophages J Immunol 2010;184; 3223–32 Borg et al Climacteric ... increase the production of IL-6 after exposure to TNF-α, IFN-γ or IL-471 IL-6 is Climacteric The role of cytokines in skin aging involved in the aging of skin and in the formation of skin wrinkles... properties of the skin2 8 CYTOKINES Cytokines play an important role in skin aging These cellsignalling proteins serve as an intercellular communication link They are produced by cells of the immune... Climacteric The role of cytokines in skin aging Climacteric Downloaded from informahealthcare.com by Linkopings University on 08/02/13 For personal use only TNF-a AND SKIN AGING In the skin, TNF-α