Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 131, Issue 8, Pages 1660-1667Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/jid.2011.123
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Funding
- Japan Science and Technology Agency
- Astellas Pharma
- Japanese Government
- Astellas Pharma in the Formation of Innovation Center for Fusion of Advanced Technologies
- Grants-in-Aid for Scientific Research [22590433, 22021022, 23229003] Funding Source: KAKEN
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G-protein coupled receptors (GPCR) exert diverse physiological functions, many of which are exploited therapeutically. The roles of GPCR in keratinocytes in immune response in the skin, however, remain poorly defined. In this study, we focused on Gi-coupled GPCR in keratinocytes and defined their actions in immunoactivation of cultured keratinocytes in vitro and immune reaction in the skin in vivo. We first activated HaCaT cells by tumor necrosis factor (TNF)-alpha and IFN-gamma and examined effects of various ligands for GPCR on production of CCL17 and CCL5. Agonists for Gi-coupled receptors, particularly GW9508 for GPR40, inhibited CCL17 and CCL5 expression in a pertussis toxin-sensitive manner. The inhibitory effect by GW9508 was abrogated by depletion of GPR40 with RNA interference. GW9508 further suppressed expression of IL-11, IL-24, and IL-33 induced in HaCaT cells by TNF-alpha and IFN-gamma. GW9508 also inhibited CCL5 and CXCL10 production by normal human epidermal keratinocytes. Administration of GW9508 topically to the skin in the challenging phase suppressed ear swelling in a repeated hapten application model and contact hypersensitivity with downregulation of CCL5 and CXCL10, respectively. Thus, in the skin, stimulation of Gi-coupled receptors attenuates induction of critical cytokines and chemokines by proinflammatory cytokines in keratinocytes and suppresses allergic inflammation in the skin.
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