IL-4 Inhibits the Melanogenesis of Normal Human Melanocytes through the JAK2–STAT6 Signaling Pathway

Abstract

Skin diseases can be characterized by their predominant CD4-positive T-helper (Th) cell profiles. Chronic dermatological conditions often give rise to abnormal skin pigmentation. To understand the role of Th cells in pigmentation, the effects of the major Th cell cytokines, IFNγ, IL-4, and IL-17A, on melanogenesis were evaluated using cultured normal human melanocytes (NHMs) instead of relying on transformed melanoma cell lines. IL-4 directly inhibited melanogenesis in NHMs and downregulated both transcription and translation of melanogenesis-associated genes, such as microphthalmia-associated transcription factor (MITF) and dopachrome tautomerase. Despite the lack of a direct inhibition of melanin pigment synthesis, IFNγ and IL-17A increased the synthesis of an antimelanogenic cytokine IL-6 in NHMs. IFNγ activated signal transducers and activators of transcription 1 (STAT1) and STAT3 phosphorylation in NHMs, and IL-4 increased the STAT3 and STAT6 phosphorylation. The differential phosphorylation profile of STAT proteins between IFNγ and IL-4 may explain the difference in their effect on melanogenesis in NHMs. The IL-4-induced downregulation of melanogenesis was inhibited by treating NHMs with a JAK2 inhibitor AG490 or STAT6 siRNA. In conclusion, the involvement of the IL-4-induced JAK2-STAT6 signaling and the IFNγ- or IL-17A-dependent antimelanogenic IL-6 production should be considered as one of the mechanisms explaining the association with hypopigmention in skin diseases.

IFN-γ signaling maintains skin pigmentation homeostasis through regulation of melanosome maturation

“…Of the pigmentation genes, DCT showed a drastic decrease of around 80%. Similar observations were also reported during the course of another study (17,18). TYRP1 and TYR were decreased to a lesser extent across different primary cultures treated with IFN-γ ( Fig.…”

HDL Induces the Expression of the M2 Macrophage Markers Arginase 1 and Fizz-1 in a STAT6-Dependent Process

“…Kaempferol is a natural polyphenol compound that has been shown to specifically block IL-4-induced STAT6 phosphorylation through the selective inhibition of JAK3 activity [29]. The canonical pathway for IL-4 induced STAT6 phosphorylation typically involves JAK1 and JAK3 [30], though JAK2 can also participate (e.g., [31]).…”

Paracrine regulation of melanogenesis

“…In various dermatological conditions, including UV irradiation‐ and immune‐ and/or inflammation‐related disorders such as vitiligo, psoriasis and atopic dermatitis, keratinocyte‐derived paracrine factors can be involved in the regulation of melanogenesis, either by single action or combined effect within the intricate cytokine network …”

“…Neighbouring cells around melanocytes, such as keratinocytes, fibroblasts and immune cells, positively or negatively influence melanogenesis by secreting paracrine factors in response to UV irradiation or inflammatory conditions (Fig. ) . Furthermore, several studies have shown that extracellular matrix (ECM) proteins, which are responsible for structure formation and the transduction of cellular signalling pathways in the skin, can affect melanogenesis .…”