Roles de los factores de inflamación en la melanogénesis 3.pdf

Molecular Medicine REPORTS 21: 1421-1430, 2020 Roles of inflammation factors in melanogenesis (Review) CHUHAN FU*, JING CHEN*, JIANYUN LU, LU YI, XIAOLIANG TONG, LIYANG KANG, SHIYAO PEI, YUJI...

Molecular Medicine REPORTS 21: 1421-1430, 2020 Roles of inflammation factors in melanogenesis (Review) CHUHAN FU*, JING CHEN*, JIANYUN LU, LU YI, XIAOLIANG TONG, LIYANG KANG, SHIYAO PEI, YUJIE OUYANG, LING JIANG, YUFANG DING, XIAOJIAO ZHAO, SI LI, YAN YANG, JINHUA HUANG and QINGHAI ZENG Department of Dermatology, Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China Received January 29, 2019; Accepted September 24, 2019 DOI: 10.3892/mmr.2020.10950 Abstract. The occurrence of hyperpigmentation or hypopig- Contents mentation after inflammation is a common condition in dermatology and cosmetology. Since the exact mechanism 1. Introduction of its occurrence is not yet known, prevention and treat- 2. Process of melanogenesis ment are troublesome. Previous studies have confirmed that 3. Signaling pathways regulating melanogenesis α‑melanocyte‑stimulating hormone, stem cell factor and other 4. Function and mechanism of inflammatory factors in regu- factors can promote melanogenesis‑related gene expression lating melanogenesis through the activation of signaling pathways. Recent studies 5. Post‑inflammatory hyperpigmentations and hypopigmenta- have revealed that a variety of inflammatory mediators can tions can be treated by regulating local inflammatory factors also participate in the regulation of melanogenesis in mela- 6. Conclusions and outlook nocytes. In this review, we summarized that interleukin‑18, interleukin‑33, granulocyte‑macrophage colony stimulating factor, interferon‑ γ, prostaglandin E2 have the effect of 1. Introduction promoting melanogenesis, while interleukin‑1, interleukin‑4, interleukin‑6, interleukin‑17 and tumor necrosis factor can A coordination system has been formed under the interac- inhibit melanogenesis. Further studies have found that these tion of various cells in the skin. For instance, the cutaneous inflammatory factors may activate or inhibit melanogen- neuron‑immune‑endocrine system consists of interaction and esis‑related signaling pathways (such as protein kinase A and coordination between keratinocytes, melanocytes and dendritic mitogen activated protein kinase) by binding to corresponding Langerhans cells in the epidermis and the components of the receptors, thereby promoting or inhibiting the expression of dermis such as mast cells, macrophages, fibroblasts and nerve melanogenesis‑related genes and regulating skin pigmenta- cells (1‑3). Allergens, pathogens, chemical stimuli, and phys- tion processes. This suggests that the development of drugs ical damage can all lead to skin inflammation (4‑7), which is a or treatment methods from the perspective of regulating defense response to exogenous or endogenous stimuli (8). Skin inflammation can provide new ideas and new targets for the inflammation plays a crucial role in the body, such as resisting treatment of pigmented dermatosis. This review outlines the the invasion of bacteria and other pathogens and promoting the current understanding of the inflammation factors' roles in repair of wounds. Recent studies have revealed that inflamma- melanogenesis. tory cytokines are closely related to skin pigmentation (9,10). Skin hyperpigmentation or hypopigmentation after inflam- mation is a clinically common symptom. Various acute or chronic inflammatory skin reactions may cause changes in skin pigmentation (11), such as psoriasis, eczema, or laser surgery. Recent studies have confirmed that interleukin (IL)‑1, IL‑4, IL‑6 and other inflammatory mediators can regulate Correspondence to: Dr Jinhua Huang or Dr Qinghai Zeng, the proliferation and differentiation of human epidermal Department of Dermatology, Third Xiangya Hospital of Central melanocytes directly or indirectly and participate in the regu- South University, 138 Tongzipo Road, Changsha, Hunan 410013, lation of melanogenesis in melanocytes (11‑13). Treatments P.R. China that modulate these inflammatory mediators may have great E‑mail: [email protected] E‑mail: [email protected] clinical utility in the treatment of some dyschromatosis (14). This review will focus on the role of inflammatory factors in * Contributed equally melanogenesis and the mechanisms involved. Key words: hypopigmentation, hyperpigmentation, inflammatory 2. Process of melanogenesis factor, melanogenesis, pigmented dermatosis Melanocytes originate from the ectodermal neural crest, migrate to the mesenchyme as the embryo develops, and 1422 FU et al: ROLES OF INFLAMMATION FACTORS IN MELANOGENESIS then further migrate to the skin, eye uveal, stria vascularis, and TNF, IL‑1 and IL‑6 can inhibit melanogenesis (37,38). In vestibular organ, endolymphatic sac and pia mater (15,16). The addition to keratinocytes, other types of cells in the skin, such as migration, proliferation, and differentiation of melanoblasts are fibroblasts, also participate in the regulation of melanocytes by mainly regulated by regulatory factors secreted by the dorsal producing paracrine factors (Fig. 2). Melanocytes interact with neural tube, ectoderm, and keratinocytes such as the fmily of these surrounding cells by expressing corresponding receptors Wingless‑type protein (WNT), endothelin 3 (EDN3), and stem on the cell surface (27). In addition, studies have revealed that cell factor (SCF) (17). Melanogenesis in mature melanocytes paracrine factors can provide a variety of mechanisms to acti- occurs in melanosomes. Melanosomes are unique organelles vate DNA repair mechanisms by activating different receptors located in the cytoplasm of melanocytes, which contain and signaling pathways to maintain melanocyte homeostasis key enzymes regulating the production of pigments such as and prevent UV mutagenesis (28). tyrosinase (TYR), tyrosinase‑related protein‑1 (TYRP‑1) and tyrosinase‑related protein‑2 (TYRP‑2) (17,18). Activation 4. Function and mechanism of inflammatory factors in of the transcription factor microphthalmia‑associated tran- regulating melanogenesis scription factor (MITF) (19‑21) results in the upregulation of the expression of key genes such as TYR, TYRP‑1 and Inflammation is a basic pathological process mainly involving TYRP‑2 (16,22,23), and promotes melanogenesis in mela- defensive reactions of living tissues with a vascular system in nocytes (17). Mature melanosomes can migrate from the response to the stimulation of various damage factors. The perinuclear region to the dendrites of melanocyte under the chemical factors involved in mediating inflammatory reactions regulation of tubulin (kinesin, dynein) (17). In the epidermis, are called chemical mediators or inflammatory mediators. The melanocytes are associated with 30 to 40 keratinocytes inflammatory mediators in the skin are mainly secreted by Th through dendrites, transferring mature melanosomes into the cells, lymphocytes, monocytes‑macrophages, dendritic cells, and cytoplasm of keratinocytes (15,24). the like. Th cells are mainly classified as Th1 and Th2 cells (39). Th1 cells play an important role in cellular immune responses, 3. Signaling pathways regulating melanogenesis secreting cytokines such as interferon‑γ (IFN‑γ), tumor necrosis factor (TNF), IL‑2, IL‑3, GM‑CSF; Th2 cells play a key part in Multiple signaling pathways are involved in the regulation of humoral immune responses, secreting IL‑4, IL‑5, IL‑10, IL‑13, melanogenesis, with the cyclic AMP (cAMP)/protein kinase A IL‑3, GM‑CSF as well as other cytokines (40,41). In a normal (PKA) signaling pathway being one of the most important body, Th1 cytokines and Th2 cytokines are in equilibrium. signaling pathways (Fig. 1). The most well‑known receptor When the body suffers from a certain disease, the balance on melanocytes that modulates their function is the melano- between Th1 and Th2 is impaired, and there is a drift toward cortin‑1 receptor (MC1R). When α‑melanocyte‑stimulating Th1 or Th2 (39). T helper cell 17 (Th17) is a newly discovered hormone (α‑MSH) binds to MC1‑R on the membrane of mela- T cell subset that secretes IL‑17, IL‑6, IL‑21 and IL‑22 and nocytes, it activates adenylate cyclase, increases intracellular participates in the occurrence of innate immunity and certain cAMP, activates PKA‑cAMP response element‑binding protein inflammations by secreting IL‑17, IL‑6 and TNF‑α. Studies (CREB) pathway, and then increases MITF, promoting mela- have revealed that keratinocytes can secrete IL‑18, TNF, IL‑1, nogenesis (25‑28). MC1R is also a major regulator of human GM‑CSF, INF‑γ, and IL‑3, fibroblasts can secrete IL‑33, TNF, pigmentation and is also a melanoma susceptibility gene (28). IL‑6, and IL‑8, and melanocytes can secrete INF‑β, IL‑1, IL‑8, In addition, signaling pathways such as mitogen activated IL‑10 and TNF‑α (37,38,42). The main inflammatory media- protein kinase (MAPK), inositol trisphosphate/diacylglycerol tors that are secreted by various types of cells in the skin are (IP3/DAG), WNT, and protein kinase C (PKC) have also been presented in Table I. Recent studies have revealed that local revealed to participate in melanogenesis. The α1 adrenergic inflammatory factors of the skin may be involved in the regula- receptor can activate the IP3/DAG pathway and increase the tion of skin pigmentation (Fig. 3). The function and mechanisms intracellular levels of PKC‑β and activate tyrosinase (29). SCF, of these inflammatory factors in regulating melanogenesis are GM‑SCF and hepatocyte growth factor (HGF) can activate presented in Table II. signaling pathways mediated by the corresponding receptor IL‑18 is produced by inflammatory stimuli in Langerhans c‑KIT, GM‑CSFR, and HGFR, leading to autophosphoryla- cells (LC), dendritic cells (DC), Kupffer cells, activated mono- tion and activation of MAP kinase, thereby phosphorylating cytes/macrophages, and keratinocytes in the epidermis (43‑45). MITF, upregulating the expression of melanogenesis‑related IL‑18 has been revealed to increase the cascade expression of enzymes (30‑32). The WNT signaling pathway can activate MITF and downstream enzymes by activating the p38/MAPK MITF‑M promoter (33‑35), thereby resulting in upregula- and PKA pathways, and thus promote melanogenesis and tion of MITF expression to further regulate melanogenesis. upregulate TYRP‑1 and TYRP‑2 expression (43,46). These Catecholamines can promote melanogenesis through the results suggest that IL‑18 may participate in the regulation of cAMP/PKA pathway, while catecholamines also mediate pigmentation by regulating melanocytes. melanogenesis through the activation of PKC‑β pathways by IL‑33 can induce mast cells to produce pro‑inflammatory α1 and β2 adrenergic receptors (29,36). cytokines and chemokines (47‑51), thereby activating macro- Skin melanogenesis is affected by the epidermal melanin phages (52‑54), CD4+T cells, basophils, dendritic cells and unit, which is mainly composed of keratinocytes and melano- neutrophils (47,55‑58), and promoting skin inflammation. It cytes. Many of the paracrine factors secreted by keratinocytes has been revealed that IL‑33 mRNA is expressed in multiple can act on melanocytes to promote or inhibit melanogenesis. For organs in humans (including the skin), and in particular, example, IL‑18, IL‑33, GM‑CSF can promote melanogenesis, relatively abundant IL‑33 mRNA is found in keratinocytes  Molecular Medicine REPORTS 21: 1421-1430, 2020 1423 Figure 1. Different signaling pathways regulating melanogenesis. Upon binding to MCIR and adrenergic receptor respectively, α‑MSH and catecholamines activate the PKA pathway by increasing cAMP. Then PKA promotes MITF expression, which controls the expression of melanogenesis‑related genes TYR, TRP‑1 and TRP‑2. Upon binding to ETR and adrenergic receptor respectively, ET‑1 and catecholamines activate the PKC pathway to promote the expres- sion of TYR, TRP‑1 and TRP‑2. Upon binding to c‑MET, GM‑CSFR, and c‑KIT and respectively, HGF, GM‑CSF, and SCF activate the MAPK pathway to promote the expression of MITF, which in turn increases the expression of TYR, TRP‑1 and TRP‑2. In addition, NO in the cytoplasm regulates MITF‑driven expression of TYR, TRP‑1 and TRP‑2 through the guanylate cyclase‑cGMP pathway. α‑MSH, α‑melanocyte‑stimulating hormone; MC1R, melanocortin‑1 receptor; ET‑1, endothelin‑1; ETR, ET‑receptor; HGF, hepatocyte growth factor; GM‑CSF, granulocyte‑macrophage colony‑stimulating factor; GM‑CSFR, granulocyte macrophage colony‑stimulating factor receptor; SCF, stem cell factor; AC, adenylate cyclase; cAMP, 3'5'‑cyclic adenosine monophosphate; PKA, protein kinase A; c‑GMP, cyclic guanosine monophosphate; IP3/DAG, inositol trisphosphate/diacylglycerol; PKC, protein kinase C; MAPK, mitogen activated protein kinase; TYR, tyrosinase; TRP‑1, tyrosinase‑related protein‑1; TRP‑2, tyrosinase‑related protein‑2. and fibroblasts (59,60). Research has revealed that IL‑33 can the number of shedding spheroid granules in primary melano- improve melanin biosynthesis in NHEM and promote the cytes (MCs), but has no effects on morphological observation expression of MITF and its downstream‑regulated tyrosine, of KCs (64). TYRP‑1, and TYRP‑2 through the activation of MAPK and As one of the most important endogenous mediators of PKA pathways (14), thereby promoting melanogenesis. immunity and inflammation, IFN‑γ is also a common secre- In addition, granulocyte‑macrophage colony‑stimulating tory cytokine in the skin (46). As a pro‑inflammatory cytokine, factor (GM‑CSF) which is produced by mononuclear macro- IFN‑γ is mainly secreted by Th1 lymphocytes, CD8+ cytotoxic phages, keratinocytes and Th cells, has been revealed to T lymphocytes and NK cells (65). Other cells, including promote melanocyte proliferation and melanin synthesis (17). antigen‑presenting cells, B cells and NKT cells, can also Wu et al revealed that increased serum levels of GM‑CSF may secrete IFN‑γ (66‑68). Recent studies have demonstrated that be used as the serum biomarkers to predict the prognosis of the local accumulation of IFN‑γ through melanocyte‑specific TCAM (transplantation of cultured autologous melanocytes) CD8+ T cells plays an important role in skin discoloration when vitiligo patients are treated (61). spots in various mouse models of vitiligo (69,70). Yang et al Prostaglandin E2 (PGE2) and PGF2α which are produced reported that increased IFN‑γ is essential for the pathogen- by fibroblasts and keratinocytes have been revealed to esis of vitiligo by inducing apoptosis of melanocytes (71). stimulate dendritic cell formation and activate tyrosinase in Natarajan et al revealed that IFN‑γ signaling blocks matura- melanocytes through their dependence on the cAMP signaling tion of melanosomes by regulating pigmentation genes (72). pathway and phospholipase C (PLC) (62,63). Ma et al revealed Moreover, IFN‑γ has been revealed to regulate melanogenesis that PGE2 is important in melanosome transfer by promoting by upregulating STAT1 phosphorylation, and its inhibiting filopodia delivery (including miniaturization of melanosome, effect can be restrained by JAK1 inhibitors. Studies have also filopodia formation, and broadening diameter of filopodia) and revealed that IFN‑γ inhibits IL‑18‑induced melanogenesis (46). 1424 FU et al: ROLES OF INFLAMMATION FACTORS IN MELANOGENESIS Figure 2. Keratinocyte‑derived factors and fibroblast‑derived factors that affect melanogenesis in melanocytes through a paracrine effect. Various factors are identified to stimulate (green arrows) or inhibit (red arrows) melanogenesis in melanocytes. Keratinocytes secret factors such as IL‑18, IL‑33, GM‑CSF, PGE2 and PGF2 to stimulate melanocyte melanogenesis as well as TNF, IL‑1α and IL‑6 to inhibit melanocyte melanogenesis. Fibroblast‑derived factors such as IL‑33, PGE2 and PGF2 stimulate melanocyte melanogenesis while TNF and IL‑6 inhibit melanocyte melanogenesis. IL‑18, interleukin‑18; IL‑33, interleukin‑33; GM‑CSF, granulocyte‑macrophage colony stimulating factor; PGE2, prostaglandin E2; PGF2, prostaglandin F2; TNF, tumor necrosis factor; IL‑1α, interleukin‑1α; IL‑6, interleukin‑6. TNF is a homotrimeric cytokine, secreted mainly by mono- transduction is initiated by binding to IL‑1 receptor type I cytes and macrophages, and also by keratinocytes, dendritic (IL‑1Rα chain) (75), which can inhibit tyrosinase activity cells, Th1, Th17 and Th22. It functions by binding to two and melanogenesis (12,74). Of its many activities, IL‑1α also different receptors: TNFR1/p55 and TNFR2/p75 (9). TNF not stimulates human fibroblasts to produce keratinocyte growth only induces inflammation through the activation of vascular factor (KGF) (76). Keratinocytes store a large amount of active endothelial cells and immune cells, but also acts as an impor- IL‑1α, express IL‑1 receptors (77) and produce more IL‑1α tant regulator of lymphoid tissue development by controlling upon ultraviolet B (UVB) exposure (78). KGF is thought to apoptosis (9). Elevated levels of TNF have been revealed at induce TYR expression in primary melanocytes (79). The sites of inflammation in several autoimmune diseases, and combination of KGF and IL‑1α increases melanin deposition inflammatory symptoms have generally decreased after and they may be involved in the initial stage of human Solar neutralization of TNF. For instance, higher expression levels lentigines lesion formation (79). Although they share only 24% of TNF, TNFR1 and TNFR2 are observed in psoriasis (73). identity in protein sequence, IL‑1β and IL‑1α fold in a highly Studies have revealed that after treatment of melanocytes with similar manner and recognize the same receptor, the type I both IL‑17 and TNF for 24‑48 h, the levels of c‑KIT, MC1‑R, IL‑1 receptor (IL‑1RI) (80). After treatment of a panel of mela- MITF, and TYRP‑2 were on the decrease, and the levels of noma cell lines with IL‑1β, it was observed that most of the tyrosinase and melanin were significantly reduced (10). It MITF‑M was inhibited and was NF‑κ B‑ and JNK‑dependent. has been revealed that, through the combination with IL‑17, The inactivation of these two pathways could eliminate the TNF can inhibit melanogenesis by PKA and MAPK signaling inhibitory effects of IL‑1β on melanin, which indicated that pathways (9,10). Blocking TNF can lead to rapid restoration IL‑1β could downregulate MITF‑M through NF‑kB and JNK of pigmentation gene expression in psoriatic lesions. This pathways, thereby inhibiting melanogenesis (74). suggests that anti‑TNF has the potential of treating pigmented IL‑4 is a cytokine mainly secreted by Th2 cells and dermatosis (10). can also be produced by CD8‑positive cytotoxic T cells, IL‑1 is an important pro‑inflammatory cytokine in innate basophils, eosinophils, and mast cells in chronic inflamma- immunity that stimulates the differentiation and function tion (81,82). IL‑4 plays a key role in the generation of the of immune surveillance cells and contributes to increased major mediator IgE in hypersensitivity as well as in the tumor invasiveness, metastasis, and angiogenesis under induction of inflammation, contributing to the autoimmunity chronic inflammatory conditions (74). IL‑1α is an inflam- of the body (83). IL‑4 is involved in the maintenance of matory mediator mainly produced by Langerhans cells, and Th2 lymphocytes and acts as an autocrine growth factor of is also secreted by melanocytes and keratinocytes. Its signal differentiated Th2 cells (84). It is hypothesized that vitiligo  Molecular Medicine REPORTS 21: 1421-1430, 2020 1425 Table I. Inflammatory mediators secreted by various types of cells in the skin. Cell type Inflammatory factors Mononuclear macrophages INF‑γ, TNF, IL‑1, GM‑CSF, IL‑6, IL‑8, IL‑12, IL‑18, IL‑10 Neutrophils IL‑1β, TNF, IL‑6, IL‑8, IL‑15, IFN‑γ Th1 cells IFN‑γ, TNF, IL‑2, IL‑3, GM‑CSF Th2 cells IL‑4, IL‑5, IL‑6, IL‑10, IL‑13, IL‑3, GM‑CSF Th17 cells IL‑17, IL‑6, IL‑21, IL‑22, TNF‑α Mast cells TNF, IL‑1, IL‑4, IL‑6, IL‑8, IL‑10, IL‑13, IFN‑γ Dendritic cells IL‑2, IL‑4, IL‑5, IL‑12, INF‑γ Keratinocytes IL‑18, TNF, IL‑1, GM‑CSF, INF‑γ, IL‑33 Melanocytes INF‑β, IL‑1, IL‑8, IL‑10, TNF‑α Fibroblasts IL‑33, TNF, IL‑6, IL‑8 Th1, T helper 1; IFN‑γ, interferon‑γ; TNF, tumor necrosis factor; IL, interleukin; GM‑CSF, granulocyte‑macrophage colony stimulating factor. Figure 3. Cytokines that inhibit or stimulate melanogenesis. Cytokines such as TNF, IL‑17 and IL‑1β inhibit melanogenesis by suppressing the PKA or MAPK pathway. While cytokines such as IL‑18, IL‑33 and GM‑CSF stimulate melanogenesis by stimulating the PKA or MAPK pathway. IL‑4 stimulates melanogenesis by stimulating the STAT pathway. PGE2, PGF2, IL‑1α and IL‑6 stimulate melanogenesis through unidentified signaling pathways. TNF, tumor necrosis factor; IL‑17, interleukin‑17; IL‑1β, interleukin‑1β; IL‑18, interleukin‑18; IL‑33, interleukin‑33; GM‑CSF, granulocyte‑macrophage colony stimulating factor; IL‑4, interleukin‑4; PGE2, prostaglandin E2; PGF2, prostaglandin F2; IL‑1α, interleukin‑1α; IL‑6, interleukin‑6; PKA, protein kinase A; MAPK, mitogen activated protein kinase; STAT, signal transducer and activator of transcription; TYR, tyrosinase; TRP‑1, tyrosinase‑related protein‑1; TRP‑2, tyrosinase‑related protein‑2. development is directly affected by the imbalance of the by regulating cell growth, survival, and differentiation (87). Th1/Th2 response (85). Nouri‑Koupaee et al revealed the Research has revealed that IL‑6 decreases tyrosinase activity Th1 and Th2 response profiles in vitiligo by assessing IFN‑γ and melanogenesis (12). and IL‑4. This study revealed significant increases in IFN‑γ IL‑17 is a pro‑inflammatory cytokine produced mainly by and marked decreases of IL‑4 in patients when compared to Th17 cells, and also by other immune cells, including neutro- controls (86). It has also been revealed that IL‑4 downregu- phils, natural killer cells, mast cells, αβ and γδT cells (88). lates the expression of MITF, TYRP‑1, and TYRP‑2 through The most well‑known function of IL‑17 is to prevent bacterial the JAK2/STAT6 signaling pathway and thus inhibits and fungal infections (88). IL‑17 has a variety of inflammatory melanogenesis (13). effects, resulting in the release of large amounts of cytokines IL‑6 is secreted by keratinocytes, epidermal cells, fibro- from a variety of cells, such as epithelial cells, endothelial blasts and dermal endothelial cells and is involved in the cells, and fibroblasts (89). Studies have revealed that IL‑17 regulation of various biological responses including immune can bind to TNF to inhibit the signaling pathway for melano- response, inflammation, hematopoiesis, and tumorigenesis genesis, thereby inhibiting melanogenesis (10). The function 1426 FU et al: ROLES OF INFLAMMATION FACTORS IN MELANOGENESIS Table II. Function and mechanisms of inflammatory factors in the regulation of melanogenesis. Effect on Factor Experimental cells melanogenesis Mechanisms (Refs.) IL‑18 Keratinocyte Promotion Increasing tyrosinase activity and upregulating (43) TYRP‑1 and TYRP‑2 expression IL‑33 Melanocytes Promotion Promoting MITF, TYR, TYRP‑1, TYRP‑2 (14) expression by activating the p38/MAPK and PKA pathways GM‑CSF Melanocytes Promotion Promoting melanocyte proliferation and melanin (17) synthesis PGE2 and PGF2α Keratinocytes Promotion Stimulating melanocyte dendrite formation (62) through a cAMP‑dependent pathway IFN‑γ B16F10 Inhibition Blocking maturation of melanosome and (46,72) upregulating STAT1 phosphorylation TNF Melanocytes, Inhibition Inhibiting melanin formation through PKA and (10) primary pooled MAPK signaling pathways in combination with human keratinocytes IL‑17 IL‑1α Primary melanocytes, Promotion Combination of KGF increases melanin deposition (79) swine skin IL‑1β Melanoma cell lines Inhibition Downregulating MITF‑M expression through (74) (LB2259‑MEL and NF‑κB and JNK pathways CP50‑MEL) IL‑4 Melanocytes Inhibition Downregulating the expression of MITF, TYRP‑1, (13) TYRP‑2 through the JAK2‑STAT6 signaling pathway IL‑6 Melanocytes Inhibition Decreasing tyrosinase activity (12) IL‑17 Melanocytes, Inhibition Inhibiting melanin formation through PKA and (10) primary pooled MAPK signaling pathways in combination with human keratinocytes TNF TYRP‑1, tyrosinase‑related protein‑1; TYRP‑2, tyrosinase‑related protein‑2; MITF, microphthalmia‑associated transcription factor; TYR, tyrosinase; PKA, protein kinase A; MAPK, mitogen activated protein kinase; JNK, c‑Jun N‑terminal kinase; JAK‑STAT, Janus kinase‑signal transducer and activator of transcription. and mechanisms of these inflammatory factors in regulating effect on tyrosine activity or melanocyte‑specific cytotoxicity melanogenesis are presented in Table II. is the decolorization mechanism (92,93). In recent years, it has It should be noted that the IFN‑γ‑related data were acquired been revealed that kojic acid also inhibits the melanogenesis from a murine melanoma model (B16F10) and IL‑1α‑related of melanocytes by promoting the expression of IL‑6 in kera- data were based on observations from porcine skin. Therefore, tinocytes. Resveratrol was revealed to play an important role whether their effects on melanogenesis in human melanocytes are in ameliorating inflammation, including skin inflammation and the same still requires confirmation by subsequent experiments. reducing inflammatory injury in HaCaT cells (94). Studies have also reported that resveratrol inhibits melanin synthesis to treat 5. Post‑inflammatory hyperpigmentations and hypo­ hyperpigmented diseases (95). Therefore, resveratrol may also pigmentations can be treated by regulating local affect melanogenesis by regulating inflammatory factors. inflammatory factors Although the causes of vitiligo are not completely clear, inflammation has been revealed to play a role in its pathogen- In clinical practice, various treatments can be effective for esis (96). Certain studies revealed that higher expression of post‑inflammatory hyperpigmentations and hypopigmentations pro‑inflammatory cytokines had an inhibitory effect on pigmen- by influencing inflammatory factors. For example, chloasma tation in vitiligo lesions (97,98). For example, Kim et al (99) is a postinflammatory hyperpigmented disease caused by revealed that increased expression of TNF‑α in keratinocytes many factors such as heredity, ultraviolet radiation, pregnancy, of the lesion area in vitiligo patients inhibited the secretion of hormone therapy, cosmetics, and phototoxic drugs (90). Kojic melanocyte growth factor from KCs. Barygina et al suggested acid, hydroquinone, and tranexamic acid are commonly used that low‑dose IL‑4, β ‑endorphin, bFGF and IL‑10 may be to treat melasma (91). It is well‑known that their inhibitory considered as new therapeutic tools for vitiligo treatment (100).  Molecular Medicine REPORTS 21: 1421-1430, 2020 1427 Studies have revealed that 308 nm excimer laser can significantly XZ, SL and YY analyzed and interpreted the data. All authors reduce the level of TNF‑α in lesions (101), thereby promoting have read and approved the final manuscript and agreed to be MC function. Various studies reported that the expression of accountable for all aspects of the work in ensuring that ques- IL‑4, TNF‑α and other inflammatory cytokines was down- tions related to the accuracy or integrity of any part of the regulated after topical application of tacrolimus in lesions of work are appropriately investigated and resolved. vitiligo (102,103). Methotrexate (MTX) is used in the treatment of autoimmune diseases to decrease T cells that produce TNF‑α, Ethics approval and consent to participate which is a key step in the development of vitiligo (104). A study by Alghamdi and Khurrum revealed that oral MTX was a safe Not applicable. and effective therapeutic approach for vitiligo, however, due to the fact that this was a small uncontrolled pilot study, further Patient consent for publication research needs to be carried out (105). Afamelanotide is a potent and longer‑lasting synthetic analogue of naturally occurring Not applicable. α‑MSH, which is decreased in vitiligo. Grimes et al (106) found that NB‑UVB combined with afamelanotide is safe and effec- Competing interests tive and that afamelanotide represents a potentially effective treatment for vitiligo, however this still requires further studies. The authors declare that they have no interests. 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