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The roles of cytokines in photoaging
Journal of Dermatological Science 23 Suppl. 1 (2000) S30 – S36 www.elsevier.com/locate/jdermsci
The roles of cytokines in photoaging Seiji Kondo * Department of Dermatology, Faculty of Medicine, Sapporo Medical Uni6ersity, S1 W 16, Chuo-ku, Sapporo 060 -8543, Japan
Abstract Photoaging comprises characteristic changes in appearance and function of the skin as a result of repeated sun exposure rather than to passage of time alone. Clinically, wrinkles, laxity, coarseness, mottled pigmentation, lentigenes, teleangiectasia and purpura characterize photoaging. Photoaging is also characterized by atrophy, fibrotic depigmented areas termed pseudoscars, and ultimately premalignant and malignant neoplasms on sun exposed areas. These features are the result of ultraviolet radiation (UVR) in the sunlight. UVR stimulates and activates various cells and tissues to produce and release cytokines that may play a significant role in the process of photoaging. However, cytokines are the major orchestrators of the host defense processes and are involved in response to exogenous and endogenous insults, and repair and restore homeostasis. Therefore, cytokines may be beneficial in the course of photoaging. Considering the complex cytokine network in the skin, focus will be taken on several subjects that have seen major changes during the last few years. I will first outline our knowledge of cytokines in the skin together with their functions, then review our knowledge of the involvement of cytokines in photoaging, and finally summarize the defense system related to cytokines. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Photoaging; Cytokine; Metalloproteinase; Reactive oxygen species
1. Cytokines and their sources in human skin UVB, 290–320 nm, is very biologically active but mostly absorbed or dissipated within the epidermis. Only a small fraction reaches the dermis. By contrast, 35–50% of incident UVA irradiation, 320 – 400 nm wavelengths, penetrates to the dermis. Furthermore, UVA is far more abundant (5.6% of the sunlight) in terrestrial sunlight than UVB (0.15% of the sunlight). Thus, UVA may
* Tel.: +81-11-6112111, ext. 3455; fax: +81-11-6133739. E-mail address: [email protected] (S. Kondo)
also play a significant role in the induction of biological changes in the skin exposed to sunlight. Cytokines are produced from almost all nucleated cells, when stimulated or activated, including KC, melanocytes, Langerhans cells in the epidermis, and fibroblasts, endothelial cells, smooth muscle cells, mast cells, lymphocytes and other inflammatory cells in the dermis (Table 1). All of them are capable of producing various cytokines, some of which are mainly induced by UVB, but both UVB and UVA regulate others. However, since little is known about the regulatory effects of UVA on the induction of cytokines from the skin cells, I will not distinguish between UVR and
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UVB or UVA in terms of the effects on cytokine induction.
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mal synthesis of KGF and epidermal overproduction of IL-8 and Groa.
2.2. Pigment anomaly 2. Epidermal alterations
2.1. Keratinocytes (KC) Histologically, chronic epidermal photodamage is characterized by variability in thickness, with alternating areas of severe atrophy and hyperplasia and often with some degree of nuclear atypia in KC. These changes are thought to reflect dysregulation of KC growth exposed to UVR. Although the cause of KC growth dysregulation in photoaged skin is not well elucidated, KCderived cytokines may be, at least, partly involved in this process. Growth promoting activity on KC is found in IL-1, IL-6, IL-8, GM-CSF, TGF-a, amphiregulin, and NGF, which are produced from KC themselves, and thus act in an autocrine or paracrine fashion. Fibroblast-derived cytokines, including KGF, EGF, and HGF stimulate KC growth as well. Mast cells and inflammatory cells are also known to produce several of these cytokines that may also contribute to the final pathological changes in sun-damaged skin. UVR has been shown to up-regulate most of these cytokines. However, ameliorating mechanisms have also been found in cytokines and cytokine/ cytokine receptor interactions. For example, some cytokines including TGF-b and TNF-a, are known to suppress KC proliferation. A study demonstrating an increase of steady-state mRNA levels of IL-1a, TNF-a and TGF-b in chronically UVB-irradiated hairless mouse skin [1] may suggest an involvement of these cytokines in the alterations of photo-damaged skin. Downregulation of cytokine receptor expression may also contribute to KC growth control. We have shown that after UVB irradiation the expression of KGF-R and CXCR-2 in human KC is decreased [2,3]. Since CXCR-2 binds IL-8 and MGSA/ Groa, both of which have a growth promoting activity for epidermal KC, downregulation of both receptors by UVB may decrease the ability of the epidermis to respond to an increased der-
Pigment anomaly may be mediated by cytokines that regulate the growth, differentiation and melanin synthesis of melanocytes. Due to their location in the skin, melanocytes are affected by cytokines derived not only from KC but also from dermal cells, including fibroblasts and inflammatory cells. Melanocyte growth-promoting activity was found in bFGF, MGSA/Groa, ET-1, HGF, and SCF, whereas TGF-b, IL-1a, IL-6, TNF-a and IFN-b have been shown to suppress melanocyte proliferation as well as the activity of melanocyte tyrosinase. Therefore, these cytokines may be responsible for pigment anomaly observed in photo-damaged skin.
2.3. Langerhans cells (LC) A statistically significant decrease of LC in actinically damaged skin has been demonstrated [4]. A subsequent electron microscopic study has revealed remarkable differences in the population, distribution and morphology of LC between photoaged and intrinsically aged facial skin and the participation of LC in cutaneous photoaging processes was suggested [5]. Although the mechanisms of these changes observed in LC have not been elucidated, cytokines affecting the viability, number, function and morphology of LC may be involved. Thus, the cytokine microenvironment in actinically damaged epidermis in terms of the presence and concentration of GM-CSF, IL-6, IL-1, TNF-a and MCP-1 may be an important factor for the alterations observed in LC.
3. Dermal alterations in photoaging The major changes in photo-damaged skin are seen in the dermis. The histologic hallmark of photoaging is a massive accumulation of elastotic material in the upper and mid-dermis, and this phenomenon is known as solar elastosis. This solar elastotic material is composed of elastin, fibrillin
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and other extracellular matrix components. Dermal changes in photoaging require extracellular matrix turnover and deposition. The regulation of the extracellular matrix involves a balance be-
Table 2 Family of matrix metalloproteinases (MMPs) Groups
Enzyme names
I
Interstitial collagenase collagen type I, II, III, (MMP-1) VII, X Neutrophil collagenase collagen type I, II, III (MMP-8)
II
72 kd gelatinase (MMP-2)
Table 1 Cytokines and their sources in human skina Cytokine
Sources
IL-1
KC, LC, mel, FB, EC, MC, T, B, neutro, mono/macro, NK T (Th1) mel, MC, T (Th1/2), neutro, eosino, NK MC, T (Th2, CD8), eosino, baso MC, Th2, eosino KC, LC, mel, FB, EC, MC, T (Th2), B, mono/macro, eosino, KC, mel, FB, EC, MC, T, mono/macro, neutro, eosino, baso, NK T (Th2), MC, B, mono/macro KC, LC, MC, B, mono/macro KC, LC, mel, FB, EC, SMC, MC, T, B, mono/macro, neutro, eosino, baso, NK KC, LC, mel, FB, EC, MC, T, B, mono/macro, eosino KC, mono/macro, eosino KC, mel, FB, SMC, MC, T, B, mono/ macro, eosino KC, FB, EC, SMC, T, macro KC, EC, mono/macro
IL-2 IL-3 IL-4 IL-5 IL-6 IL-8 IL-10 IL-12 TNF-a GM-CSF TGF-a TGF-b BFGF PDGF Chemokines C-C MIP-1a MIP-1b RANTES MCP-1/ MCAF C-X-C MGSA/Groa KGF NGF SCF VEGF IFN-g ET-1 HGF IGF a
LC, FB, EC, SMC, MC, T, B, mono/ macro, neutro, eosino MC, T, B, mono/macro KC, FB, EC, T, mono/macro, baso KC, mel, EC, mono/macro
KC, FB, T, mono, neutro, FB, SMC KC, FB, SMC, MC, T, macro KC, FB, EC, MC, macro KC, SMC, macro MC, T (Th1, CD8), NK KC, FB, EC, SMC, mono/macro EC, SMC, T, macro FB, SMC, macro, neutro
KC, keratinocytes; LC, Langerhans cells; mel, melanocytes; FB, fibroblasts; EC, endothelial cells; SMC, smooth muscle cells; MC, mast cells; neutro, neutrophils; mono, monocytes; macro, macrophages; eosino, eosinophils; baso, basophils; NK, natural killer cells.
92 kd gelatinase (MMP-9) III
Stromelysin-1 (MMP3) Stromelysin-2 (MMP10) Matrylysin (MMP-7)
Matrix substrates
gelatin type I, collagen type IV, V, VII, X, fibronectin, elastin gelatin type I, V, collagen type IV, V, fibronectin, elastin proteoglycans, fibronectin, laminin gelatins I, III, IV, V gelatins I, III, IV, V, fibronectin gelatins I, III, IV, V, proteoglycans, fibronectin, elastin
tween synthesis of its structural components and their degradation by metalloenzymes (matrixmetalloproteinases, MMPs), the activities of which are, in turn, modulated by the specific tissue inhibitors of MMPs (TIMPs). Thus far, MMPs have been divided into three subclasses with respect to their substrate specificity (Table 2): (a) collagenases that can cleave native triple helical collagens into characteristic fragments that denature and can be further degraded by unspecific proteases as well as MMPs; (b) 72 and 92 kd IV collagenases (gelatinases), which degrade basement membrane collagens as well as denatured collagens and gelatins; and (c) the stromelysins that have a wider substrate specificity and are active on gelatins, fibronectin, proteoglycans, and laminin. Dermal alterations, including elastosis and changes in collagen and ground substances appear to be dependent on the growth and differentiation of dermal fibroblasts that are regulated by various factors such as cytokines released from infiltrating cells and epidermal cells as well as fibroblasts themselves in an autocrine or paracrine fashion.
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To date, numerous studies suggest that fibroblastgrowth regulating cytokines such as TGF-a, TGF-b, PDGF, FGF, IL-1, IL-6, and TNF-a likely control both the connective tissue formation and remodeling phases of dermal fibrotic repair.
3.1. Elastosis Elastosis is a prototypical feature of actinically damaged skin [6] and is seen as wrinkles in humans exposed to UVR during a period of many years. An accumulation of elastotic tissue components has been reported in photodamaged skin where elastin and fibrillin deposition is increased compared with unexposed sites from the same individual [7]. Fibroblasts play an important role in production of elastin, collagen, and ground substances such as glycosaminoglycans and proteoglycans. Like KC and melanocytes, fibroblasts are also influenced by cytokines that partially regulate their synthesis of structural proteins for the extracellular matrix and partially regulate their synthesis of proteases and protease inhibitors that modify these structural proteins. TGF-b and IL-1 induce elastin gene expression. The role of UV-induced elastin promoter activation in photoaging has been demonstrated using a transgenic mouse model [8]. They demonstrated that TGF-b1 and IL-1b regulate elastin gene expression in the skin. TGF-b, IL-1 as well as TNF-a and PDGF stimulate gelatinases and matrilysin. By contrast IL-4 and IFN-g inhibit metalloproteinases.
3.2. Changes in collagen Changes in collagen metabolism have been brought into focus as a major factor leading to photoaging. Specifically, it has been demonstrated that accumulation of elastotic material is accompanied by concomitant degeneration of the surrounding collagenous meshwork that is regulated by MMPs. It has been demonstrated in human skin that multiple exposures to UVR lead to sustained elevation of MMPs that degrade skin collagen and it has been suggested that MMPs contribute to photoaging. Therefore, although several cytokines, including so-called fibrogenic
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cytokines and IFN-g regulate collagen synthesis [9], dermal alterations observed in photo-aged skin are mainly regulated by the amount of MMPs and TIMPs. MMPs and TIMPs are synthesized in fibroblasts and macrophages [10–12]. Human epidermis has also been shown to produce MMPs (MMP-1, -2, -9, -10) [13,14]. Synthesis of the MMPs and TIMPs is modulated by cytokines [15–19]. MMP-1 (collagenase) production from fibroblasts is induced by IL-1, IL-6, PDGF and TNF-a [15,17,20]. MMP-1 production is also stimulated by TGF-b, bFGF and EGF. Furthermore, GM-CSF, when added with either TNF-a or IL-1b also induces MMPs. On the other hand, MMPs production is inhibited by IL-4 [21], which is a chemoattractant for fibroblasts [22] and induces dermal fibroblasts to secrete extracellular matrix proteins, such as type I and type III collagens and fibronectin [23–25]. IL-1 has been demonstrated to stimulate TIMPs production from fibroblasts [17]. EGF and bFGF also induce TIMPs from human fibroblasts and TGF-b seems to modulate the action of these growth factors on MMPs and TIMPs expression [18]. Like TGF-b, PDGF has also been demonstrated to increase other cytokines’ effects on MMPs [26]. Therefore, TGF-b and PDGF are important components in the maintenance of the proper balance among the process of tissue remodeling and repair, in which many cytokines are individually involved.
3.3. Changes in ground substances Biochemical changes in ground substance of photodamaged dermis include increased glycosaminoglycans and proteoglycan complexes [27,28]. TGF-b and PDGF induce an increase in production and secretion of proteoglycans in fibroblasts [29]. Stromelysins are metalloproteinases that are involved in the degradation of ground substances. The balance between factors that induce synthesis of new protein and factors that inhibit synthesis and destroy the extracellular protein finally determines the processes of photoaging. Therefore, cytokine dysregulation resulting in a perturbation of cooperative production may contribute to the process of photoaging.
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IL-1 and TNF-a, which also increase the rate of degradation of proteoglycans, inhibit proteoglycan biosynthesis [30]. By contrast, TGF-b and IGF-1 have the opposite effect and, thus induce proteoglycan synthesis. A study of the combination effects of cytokines on the production of proteoglycans in confluent cultures of fibroblasts has demonstrated that TGF-b is the only cytokine which increases proteoglycan production alone, but that the combination of EGF, TGF-b and PDGF induces a further increase in production and secretion [29]. TGF-a, EGF and TNF-a induce stromelysins. Thus, cytokines cooperate to produce a proper physiological response that is needed by the organism during physiological and pathophysiological remodeling.
4. Defense system Reactive oxygen species (ROS) are generated by UVR, leading to enhanced oxidative damage in chronically sun-exposed skin [31]. Superoxide dismutase (SOD), catalase and glutathione peroxidase-reductase are antioxidative enzymes that are important defensive mechanisms to survive the insults of solar damage. They act as selective scavengers for ROS produced by UVR and protect the membrane lipoproteins from photodamage. Another antioxidative activity is found in metallothionein [32], which acts as a free radical
Fig. 1. Regulation of photoaging by cytokines. Photoaging is regulated by a delicate balance between the deleterious effects of cytokines leading to photoaging and their beneficial effects ameliorating UVR-caused damage. TGF-b and PDGF are two major cytokines to modulate dermal alterations in photodamaged skin. TNF-a, IL-1 and IL-6 may play an important role in the maintenance of bodily homeostasis in actinically damaged skin.
scavenger, and thus play an important role in the protection against photoaging. These defense systems are partly regulated by cytokines. TNF-a and IL-6 have been shown to induce metallothionein and Mn-SOD in the liver of rat [33]. Metallothionein in bovine endothelial cells is induced by IL-1b, IL-6, TNF-a, TGF-b and ET-1 [34]. The induction of Mn-SOD in fibroblasts and other cell types by TNF-a [35], IL-1a [36] and IFN-g [37] has been reported. IFN-g has also been shown to enhance expression of extracellular SOD in human fibroblasts [38]. A recent study demonstrated that KGF induces glutathione peroxidase in human KC suggesting a preventive role of KGF against oxygen toxicity in the skin [39]. ROS generation of human neutrophils and lymphocytes were increased by TNFa but IFN-g decreases ROS generation and increases SOD [40]. Therefore, the balance between ROS and SOD is regulated by complex interactions of cytokines. Considering that the production of these cytokines from skin cells is modulated by UVR, it is reasonable to speculate that UVR not only causes photodamage but also plays a protective role in the process of photoaging. In fact, an antioxidant response of Mn-SOD following repetitive UVA irradiation has been demonstrated in human dermal fibroblasts [41].
5. Conclusion The effects of cytokines are different depending not only on their concentrations but also on timing and the sites of the body where they work. Therefore, their quantity and kinetics are key factors to elucidate to what extent cytokines regulate pathophysiological conditions. In some cases they have beneficial effects in the maintenance of bodily homeostasis, but in other cases even with the same amount but with a different timing or body condition, they may have deleterious effects and contribute to the induction of pathological consequences. Other characteristic features of cytokines are their ability to stimulate or inhibit the production and function of other cytokines and their synergistic and antagonistic interactive ability to form complex cytokine networks by which
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biological responses are regulated. Thus, there appears to be a delicate balance between the deleterious effects of cytokines leading to photoaging and their beneficial effects ameliorating UVR-caused damage (Fig. 1).
Acknowledgements Supported in part by Grant-in-Aid for Scientific Research from the Ministry of Education of Japan (no. 10670800).
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The roles of cytokines in photoaging Seiji Kondo * Department of Dermatology, Faculty of Medicine, Sapporo Medical Uni6ersity, S1 W 16, Chuo-ku, Sapporo 060 -8543, Japan
Abstract Photoaging comprises characteristic changes in appearance and function of the skin as a result of repeated sun exposure rather than to passage of time alone. Clinically, wrinkles, laxity, coarseness, mottled pigmentation, lentigenes, teleangiectasia and purpura characterize photoaging. Photoaging is also characterized by atrophy, fibrotic depigmented areas termed pseudoscars, and ultimately premalignant and malignant neoplasms on sun exposed areas. These features are the result of ultraviolet radiation (UVR) in the sunlight. UVR stimulates and activates various cells and tissues to produce and release cytokines that may play a significant role in the process of photoaging. However, cytokines are the major orchestrators of the host defense processes and are involved in response to exogenous and endogenous insults, and repair and restore homeostasis. Therefore, cytokines may be beneficial in the course of photoaging. Considering the complex cytokine network in the skin, focus will be taken on several subjects that have seen major changes during the last few years. I will first outline our knowledge of cytokines in the skin together with their functions, then review our knowledge of the involvement of cytokines in photoaging, and finally summarize the defense system related to cytokines. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Photoaging; Cytokine; Metalloproteinase; Reactive oxygen species
1. Cytokines and their sources in human skin UVB, 290–320 nm, is very biologically active but mostly absorbed or dissipated within the epidermis. Only a small fraction reaches the dermis. By contrast, 35–50% of incident UVA irradiation, 320 – 400 nm wavelengths, penetrates to the dermis. Furthermore, UVA is far more abundant (5.6% of the sunlight) in terrestrial sunlight than UVB (0.15% of the sunlight). Thus, UVA may
* Tel.: +81-11-6112111, ext. 3455; fax: +81-11-6133739. E-mail address: [email protected] (S. Kondo)
also play a significant role in the induction of biological changes in the skin exposed to sunlight. Cytokines are produced from almost all nucleated cells, when stimulated or activated, including KC, melanocytes, Langerhans cells in the epidermis, and fibroblasts, endothelial cells, smooth muscle cells, mast cells, lymphocytes and other inflammatory cells in the dermis (Table 1). All of them are capable of producing various cytokines, some of which are mainly induced by UVB, but both UVB and UVA regulate others. However, since little is known about the regulatory effects of UVA on the induction of cytokines from the skin cells, I will not distinguish between UVR and
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UVB or UVA in terms of the effects on cytokine induction.
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mal synthesis of KGF and epidermal overproduction of IL-8 and Groa.
2.2. Pigment anomaly 2. Epidermal alterations
2.1. Keratinocytes (KC) Histologically, chronic epidermal photodamage is characterized by variability in thickness, with alternating areas of severe atrophy and hyperplasia and often with some degree of nuclear atypia in KC. These changes are thought to reflect dysregulation of KC growth exposed to UVR. Although the cause of KC growth dysregulation in photoaged skin is not well elucidated, KCderived cytokines may be, at least, partly involved in this process. Growth promoting activity on KC is found in IL-1, IL-6, IL-8, GM-CSF, TGF-a, amphiregulin, and NGF, which are produced from KC themselves, and thus act in an autocrine or paracrine fashion. Fibroblast-derived cytokines, including KGF, EGF, and HGF stimulate KC growth as well. Mast cells and inflammatory cells are also known to produce several of these cytokines that may also contribute to the final pathological changes in sun-damaged skin. UVR has been shown to up-regulate most of these cytokines. However, ameliorating mechanisms have also been found in cytokines and cytokine/ cytokine receptor interactions. For example, some cytokines including TGF-b and TNF-a, are known to suppress KC proliferation. A study demonstrating an increase of steady-state mRNA levels of IL-1a, TNF-a and TGF-b in chronically UVB-irradiated hairless mouse skin [1] may suggest an involvement of these cytokines in the alterations of photo-damaged skin. Downregulation of cytokine receptor expression may also contribute to KC growth control. We have shown that after UVB irradiation the expression of KGF-R and CXCR-2 in human KC is decreased [2,3]. Since CXCR-2 binds IL-8 and MGSA/ Groa, both of which have a growth promoting activity for epidermal KC, downregulation of both receptors by UVB may decrease the ability of the epidermis to respond to an increased der-
Pigment anomaly may be mediated by cytokines that regulate the growth, differentiation and melanin synthesis of melanocytes. Due to their location in the skin, melanocytes are affected by cytokines derived not only from KC but also from dermal cells, including fibroblasts and inflammatory cells. Melanocyte growth-promoting activity was found in bFGF, MGSA/Groa, ET-1, HGF, and SCF, whereas TGF-b, IL-1a, IL-6, TNF-a and IFN-b have been shown to suppress melanocyte proliferation as well as the activity of melanocyte tyrosinase. Therefore, these cytokines may be responsible for pigment anomaly observed in photo-damaged skin.
2.3. Langerhans cells (LC) A statistically significant decrease of LC in actinically damaged skin has been demonstrated [4]. A subsequent electron microscopic study has revealed remarkable differences in the population, distribution and morphology of LC between photoaged and intrinsically aged facial skin and the participation of LC in cutaneous photoaging processes was suggested [5]. Although the mechanisms of these changes observed in LC have not been elucidated, cytokines affecting the viability, number, function and morphology of LC may be involved. Thus, the cytokine microenvironment in actinically damaged epidermis in terms of the presence and concentration of GM-CSF, IL-6, IL-1, TNF-a and MCP-1 may be an important factor for the alterations observed in LC.
3. Dermal alterations in photoaging The major changes in photo-damaged skin are seen in the dermis. The histologic hallmark of photoaging is a massive accumulation of elastotic material in the upper and mid-dermis, and this phenomenon is known as solar elastosis. This solar elastotic material is composed of elastin, fibrillin
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and other extracellular matrix components. Dermal changes in photoaging require extracellular matrix turnover and deposition. The regulation of the extracellular matrix involves a balance be-
Table 2 Family of matrix metalloproteinases (MMPs) Groups
Enzyme names
I
Interstitial collagenase collagen type I, II, III, (MMP-1) VII, X Neutrophil collagenase collagen type I, II, III (MMP-8)
II
72 kd gelatinase (MMP-2)
Table 1 Cytokines and their sources in human skina Cytokine
Sources
IL-1
KC, LC, mel, FB, EC, MC, T, B, neutro, mono/macro, NK T (Th1) mel, MC, T (Th1/2), neutro, eosino, NK MC, T (Th2, CD8), eosino, baso MC, Th2, eosino KC, LC, mel, FB, EC, MC, T (Th2), B, mono/macro, eosino, KC, mel, FB, EC, MC, T, mono/macro, neutro, eosino, baso, NK T (Th2), MC, B, mono/macro KC, LC, MC, B, mono/macro KC, LC, mel, FB, EC, SMC, MC, T, B, mono/macro, neutro, eosino, baso, NK KC, LC, mel, FB, EC, MC, T, B, mono/macro, eosino KC, mono/macro, eosino KC, mel, FB, SMC, MC, T, B, mono/ macro, eosino KC, FB, EC, SMC, T, macro KC, EC, mono/macro
IL-2 IL-3 IL-4 IL-5 IL-6 IL-8 IL-10 IL-12 TNF-a GM-CSF TGF-a TGF-b BFGF PDGF Chemokines C-C MIP-1a MIP-1b RANTES MCP-1/ MCAF C-X-C MGSA/Groa KGF NGF SCF VEGF IFN-g ET-1 HGF IGF a
LC, FB, EC, SMC, MC, T, B, mono/ macro, neutro, eosino MC, T, B, mono/macro KC, FB, EC, T, mono/macro, baso KC, mel, EC, mono/macro
KC, FB, T, mono, neutro, FB, SMC KC, FB, SMC, MC, T, macro KC, FB, EC, MC, macro KC, SMC, macro MC, T (Th1, CD8), NK KC, FB, EC, SMC, mono/macro EC, SMC, T, macro FB, SMC, macro, neutro
KC, keratinocytes; LC, Langerhans cells; mel, melanocytes; FB, fibroblasts; EC, endothelial cells; SMC, smooth muscle cells; MC, mast cells; neutro, neutrophils; mono, monocytes; macro, macrophages; eosino, eosinophils; baso, basophils; NK, natural killer cells.
92 kd gelatinase (MMP-9) III
Stromelysin-1 (MMP3) Stromelysin-2 (MMP10) Matrylysin (MMP-7)
Matrix substrates
gelatin type I, collagen type IV, V, VII, X, fibronectin, elastin gelatin type I, V, collagen type IV, V, fibronectin, elastin proteoglycans, fibronectin, laminin gelatins I, III, IV, V gelatins I, III, IV, V, fibronectin gelatins I, III, IV, V, proteoglycans, fibronectin, elastin
tween synthesis of its structural components and their degradation by metalloenzymes (matrixmetalloproteinases, MMPs), the activities of which are, in turn, modulated by the specific tissue inhibitors of MMPs (TIMPs). Thus far, MMPs have been divided into three subclasses with respect to their substrate specificity (Table 2): (a) collagenases that can cleave native triple helical collagens into characteristic fragments that denature and can be further degraded by unspecific proteases as well as MMPs; (b) 72 and 92 kd IV collagenases (gelatinases), which degrade basement membrane collagens as well as denatured collagens and gelatins; and (c) the stromelysins that have a wider substrate specificity and are active on gelatins, fibronectin, proteoglycans, and laminin. Dermal alterations, including elastosis and changes in collagen and ground substances appear to be dependent on the growth and differentiation of dermal fibroblasts that are regulated by various factors such as cytokines released from infiltrating cells and epidermal cells as well as fibroblasts themselves in an autocrine or paracrine fashion.
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To date, numerous studies suggest that fibroblastgrowth regulating cytokines such as TGF-a, TGF-b, PDGF, FGF, IL-1, IL-6, and TNF-a likely control both the connective tissue formation and remodeling phases of dermal fibrotic repair.
3.1. Elastosis Elastosis is a prototypical feature of actinically damaged skin [6] and is seen as wrinkles in humans exposed to UVR during a period of many years. An accumulation of elastotic tissue components has been reported in photodamaged skin where elastin and fibrillin deposition is increased compared with unexposed sites from the same individual [7]. Fibroblasts play an important role in production of elastin, collagen, and ground substances such as glycosaminoglycans and proteoglycans. Like KC and melanocytes, fibroblasts are also influenced by cytokines that partially regulate their synthesis of structural proteins for the extracellular matrix and partially regulate their synthesis of proteases and protease inhibitors that modify these structural proteins. TGF-b and IL-1 induce elastin gene expression. The role of UV-induced elastin promoter activation in photoaging has been demonstrated using a transgenic mouse model [8]. They demonstrated that TGF-b1 and IL-1b regulate elastin gene expression in the skin. TGF-b, IL-1 as well as TNF-a and PDGF stimulate gelatinases and matrilysin. By contrast IL-4 and IFN-g inhibit metalloproteinases.
3.2. Changes in collagen Changes in collagen metabolism have been brought into focus as a major factor leading to photoaging. Specifically, it has been demonstrated that accumulation of elastotic material is accompanied by concomitant degeneration of the surrounding collagenous meshwork that is regulated by MMPs. It has been demonstrated in human skin that multiple exposures to UVR lead to sustained elevation of MMPs that degrade skin collagen and it has been suggested that MMPs contribute to photoaging. Therefore, although several cytokines, including so-called fibrogenic
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cytokines and IFN-g regulate collagen synthesis [9], dermal alterations observed in photo-aged skin are mainly regulated by the amount of MMPs and TIMPs. MMPs and TIMPs are synthesized in fibroblasts and macrophages [10–12]. Human epidermis has also been shown to produce MMPs (MMP-1, -2, -9, -10) [13,14]. Synthesis of the MMPs and TIMPs is modulated by cytokines [15–19]. MMP-1 (collagenase) production from fibroblasts is induced by IL-1, IL-6, PDGF and TNF-a [15,17,20]. MMP-1 production is also stimulated by TGF-b, bFGF and EGF. Furthermore, GM-CSF, when added with either TNF-a or IL-1b also induces MMPs. On the other hand, MMPs production is inhibited by IL-4 [21], which is a chemoattractant for fibroblasts [22] and induces dermal fibroblasts to secrete extracellular matrix proteins, such as type I and type III collagens and fibronectin [23–25]. IL-1 has been demonstrated to stimulate TIMPs production from fibroblasts [17]. EGF and bFGF also induce TIMPs from human fibroblasts and TGF-b seems to modulate the action of these growth factors on MMPs and TIMPs expression [18]. Like TGF-b, PDGF has also been demonstrated to increase other cytokines’ effects on MMPs [26]. Therefore, TGF-b and PDGF are important components in the maintenance of the proper balance among the process of tissue remodeling and repair, in which many cytokines are individually involved.
3.3. Changes in ground substances Biochemical changes in ground substance of photodamaged dermis include increased glycosaminoglycans and proteoglycan complexes [27,28]. TGF-b and PDGF induce an increase in production and secretion of proteoglycans in fibroblasts [29]. Stromelysins are metalloproteinases that are involved in the degradation of ground substances. The balance between factors that induce synthesis of new protein and factors that inhibit synthesis and destroy the extracellular protein finally determines the processes of photoaging. Therefore, cytokine dysregulation resulting in a perturbation of cooperative production may contribute to the process of photoaging.
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IL-1 and TNF-a, which also increase the rate of degradation of proteoglycans, inhibit proteoglycan biosynthesis [30]. By contrast, TGF-b and IGF-1 have the opposite effect and, thus induce proteoglycan synthesis. A study of the combination effects of cytokines on the production of proteoglycans in confluent cultures of fibroblasts has demonstrated that TGF-b is the only cytokine which increases proteoglycan production alone, but that the combination of EGF, TGF-b and PDGF induces a further increase in production and secretion [29]. TGF-a, EGF and TNF-a induce stromelysins. Thus, cytokines cooperate to produce a proper physiological response that is needed by the organism during physiological and pathophysiological remodeling.
4. Defense system Reactive oxygen species (ROS) are generated by UVR, leading to enhanced oxidative damage in chronically sun-exposed skin [31]. Superoxide dismutase (SOD), catalase and glutathione peroxidase-reductase are antioxidative enzymes that are important defensive mechanisms to survive the insults of solar damage. They act as selective scavengers for ROS produced by UVR and protect the membrane lipoproteins from photodamage. Another antioxidative activity is found in metallothionein [32], which acts as a free radical
Fig. 1. Regulation of photoaging by cytokines. Photoaging is regulated by a delicate balance between the deleterious effects of cytokines leading to photoaging and their beneficial effects ameliorating UVR-caused damage. TGF-b and PDGF are two major cytokines to modulate dermal alterations in photodamaged skin. TNF-a, IL-1 and IL-6 may play an important role in the maintenance of bodily homeostasis in actinically damaged skin.
scavenger, and thus play an important role in the protection against photoaging. These defense systems are partly regulated by cytokines. TNF-a and IL-6 have been shown to induce metallothionein and Mn-SOD in the liver of rat [33]. Metallothionein in bovine endothelial cells is induced by IL-1b, IL-6, TNF-a, TGF-b and ET-1 [34]. The induction of Mn-SOD in fibroblasts and other cell types by TNF-a [35], IL-1a [36] and IFN-g [37] has been reported. IFN-g has also been shown to enhance expression of extracellular SOD in human fibroblasts [38]. A recent study demonstrated that KGF induces glutathione peroxidase in human KC suggesting a preventive role of KGF against oxygen toxicity in the skin [39]. ROS generation of human neutrophils and lymphocytes were increased by TNFa but IFN-g decreases ROS generation and increases SOD [40]. Therefore, the balance between ROS and SOD is regulated by complex interactions of cytokines. Considering that the production of these cytokines from skin cells is modulated by UVR, it is reasonable to speculate that UVR not only causes photodamage but also plays a protective role in the process of photoaging. In fact, an antioxidant response of Mn-SOD following repetitive UVA irradiation has been demonstrated in human dermal fibroblasts [41].
5. Conclusion The effects of cytokines are different depending not only on their concentrations but also on timing and the sites of the body where they work. Therefore, their quantity and kinetics are key factors to elucidate to what extent cytokines regulate pathophysiological conditions. In some cases they have beneficial effects in the maintenance of bodily homeostasis, but in other cases even with the same amount but with a different timing or body condition, they may have deleterious effects and contribute to the induction of pathological consequences. Other characteristic features of cytokines are their ability to stimulate or inhibit the production and function of other cytokines and their synergistic and antagonistic interactive ability to form complex cytokine networks by which
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biological responses are regulated. Thus, there appears to be a delicate balance between the deleterious effects of cytokines leading to photoaging and their beneficial effects ameliorating UVR-caused damage (Fig. 1).
Acknowledgements Supported in part by Grant-in-Aid for Scientific Research from the Ministry of Education of Japan (no. 10670800).
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