title: 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.
authors.affiliation: Bioscience Institute, AmorePacific Corporation R&D Center, Yongin, Gyeounggi-do, Republic of Korea.
authors.forename: Hyun
authors.initials: H
authors.lastname: Choi
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Choi
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Han
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Jin
authors.forename: Ju-Yearl
authors.initials: JY
authors.lastname: Park
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Shin
authors.forename: Tae Ryong
authors.initials: TR
authors.lastname: Lee
authors.forename: Kwangmi
authors.initials: K
authors.lastname: Kim
authors.forename: Ai-Young
authors.initials: AY
authors.lastname: Lee
authors.forename: Minsoo
authors.initials: M
authors.lastname: Noh
mesh_terms: D027682:Cation Transport Proteins / Q000235:genetics; D052816:Foreskin / Q000166:cytology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D017496:Hypopigmentation / Q000378:metabolism / Q000503:physiopathology*; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D020381:Interleukin-17 / Q000378:metabolism / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism*; D008297:Male; D008543:Melanins / Q000096:biosynthesis / Q000235:genetics; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012880:Skin Pigmentation / Q000502:physiology; D014357:Trypsin / Q000235:genetics; D058951:gp100 Melanoma Antigen / Q000235:genetics; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D007371:Interferon-gamma; D020381:Interleukin-17; D015847:Interleukin-4; D015850:Interleukin-6; D053614:Janus Kinase 2; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; D014357:Trypsin; D058951:gp100 Melanoma Antigen; D000099236:Solute Carrier Family 11, Member 2; C508717:IL17A protein, human; C508598:IL4 protein, human; C508600:IL6 protein, human; C497234:MITF protein, human; C548637:PMEL protein, human; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C494101:STAT6 protein, human; C507924:JAK2 protein, human; C489303:PRSS1 protein, human