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

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, o...

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Published in:Journal of investigative dermatology Vol. 133; no. 2; pp. 528 - 536
Main Authors: Choi, Hyun, Choi, Hyunjung, Han, Jiyeon, Jin, Sun Hee, Park, Ju-Yearl, Shin, Dong Wook, Lee, Tae Ryong, Kim, Kwangmi, Lee, Ai-Young, Noh, Minsoo
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01.02.2013
Elsevier Limited
Subjects:
Cation Transport Proteins - genetics
Foreskin - cytology
Gene Expression - drug effects
Gene Expression - physiology
gp100 Melanoma Antigen - genetics
Humans
Hypopigmentation - metabolism
Hypopigmentation - physiopathology
Interferon-gamma - metabolism
Interferon-gamma - pharmacology
Interleukin-17 - metabolism
Interleukin-17 - pharmacology
Interleukin-4 - metabolism
Interleukin-4 - pharmacology
Interleukin-6 - metabolism
Janus Kinase 2 - metabolism
Male
Melanins - biosynthesis
Melanins - genetics
Melanocytes - cytology
Melanocytes - drug effects
Melanocytes - metabolism
Microphthalmia-Associated Transcription Factor - genetics
Primary Cell Culture
RNA, Small Interfering - genetics
Signal Transduction - drug effects
Signal Transduction - physiology
Skin Pigmentation - physiology
STAT1 Transcription Factor - metabolism
STAT3 Transcription Factor - metabolism
STAT6 Transcription Factor - genetics
STAT6 Transcription Factor - metabolism
Trypsin - genetics
ISSN:0022-202X, 1523-1747, 1523-1747
Online Access:Get full text
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Summary: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.
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ISSN:0022-202X
1523-1747
1523-1747
DOI:10.1038/jid.2012.331