A GPR40 agonist GW9508 suppresses CCL5, CCL17, and CXCL10 induction in keratinocytes and attenuates cutaneous immune inflammation.

Abstract

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)-α and IFN-γ 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-α and IFN-γ. 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.

• Authors: Tomoko Fujita, Toshiyuki Matsuoka, Tetsuya Honda, Kenji Kabashima, Takako Hirata, Shuh Narumiya
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 131 Issue 8 Pg. 1660-7 (Aug 2011) ISSN: 1523-1747 [Electronic] United States
• PMID: 21593768 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCL17 protein, human
• CCL5 protein, human
• CXCL10 protein, human
• Ccl17 protein, mouse
• Ccl5 protein, mouse
• Chemokine CCL17
• Chemokine CCL5
• Chemokine CXCL10
• Cxcl10 protein, mouse
• FFAR1 protein, human
• Ffar1 protein, mouse
• GW9508
• Methylamines
• Propionates
• Receptors, G-Protein-Coupled

Topics

• Animals
• Cell Line
• Chemokine CCL17 (genetics, immunology)
• Chemokine CCL5 (genetics, immunology)
• Chemokine CXCL10 (genetics, immunology)
• Dermatitis, Contact (drug therapy, immunology)
• Female
• Gene Expression (drug effects, immunology)
• Humans
• Keratinocytes (cytology, drug effects, immunology)
• Methylamines (pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Propionates (pharmacology)
• Receptors, G-Protein-Coupled (agonists)