IL-17 and TNF Synergistically Modulate Cytokine Expression while Suppressing Melanogenesis: Potential Relevance to Psoriasis

Abstract

Inflammation-associated pigmentation changes are extremely common, but the etiology behind this clinical observation remains elusive. Particularly, it is unclear how the myriad of cytokines known to be involved in inflammatory skin processes affect epidermal melanocytes. We sought to determine how IL-17 and TNF influence normal human melanocytes, as these two cytokines have been implicated in various skin diseases. IL-17 and TNF jointly stimulated broad inductions of cytokines , including melanoma mitogens CXCL1 and IL-8. Moreover, IL-17 and TNF synergistically inhibited pigmentation-related signaling and melanin production, and induced keratinocytes production of β-defensin 3, an antagonist for melanocortin-receptor 1. When analyzing psoriasis lesions that are known to over express IL-17 and TNF, we observed an increase in melanocyte number and a simultaneous decrease in pigmentation signaling. Furthermore, therapeutic neutralization of TNF and IL-17 with mAbs results in a rapid recovery of pigment gene expression in psoriasis lesions. These results demonstrate that IL-17 and TNF can impact both the growth and pigment production of melanocytes, which may contribute to the pigmentation changes associated with psoriasis. These findings may allow the development of novel therapeutics for pigmentary disorders and bring new insights into the immune milieu surrounding melanocytes and related neoplasms.

Increased Activity and Number of Epidermal Melanocytes in Lesional Psoriatic Skin

“…There is evidence of melanocyte activation, such as increase in their size, intense labelling and marked elongation and increase in the number of their dendrites with all used MoAbs, similar to findings previously reported with Melan A. These features have been attributed to an influence by the cytokines interleukin 17 and tumour necrosis factor α [10]. In our study, the activation marker HMB45 revealed a 3-fold increase in melanocytes of the psoriatic lesions, thus confirming the aforementioned morphological cell activation signs.…”

“…Circulating mediators known to contribute to inflammation in psoriatic skin are likely to affect the neighbouring epidermal and dermal cells, such as melanocytes and papillary blood vessels [10]. …”

Transient TNF regulates the self-renewing capacity of stem-like label-retaining cells in sphere and skin equivalent models of melanoma

“…For example, TNF was shown to induce the reversible dedifferentiation of melanoma cells [35] and an increased melanocyte number while inhibiting their differentiation-related pigmentation [68]. Similarly, TNF promotes neural stem (NSC) cell proliferation but inhibits their differentiation [69] and maintains osteosarcomas in their undifferentiated state [70].…”

Melanocytes and Their Diseases

“…Most of these acquired hypopigmentation disorders are associated with inflammation and a recent study shows that TNF-a and IL-17 synergistically suppress pigmentation-related signaling and melanin production partly via MC1R (Wang et al 2013). Hypopigmentation is also related with other syndromes (such as ataxia telangiectasia, Alezzandrini syndrome, Preus syndrome, Tietz syndrome, tuberous sclerosis, Rothmund-Thomson syndrome, and Werner syndrome) and infections (such as HIV, Hansen's disease, Malassezia furfur, and syphilis).…”