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 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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