Gαq controls rheumatoid arthritis via regulation of Th17 differentiation.
Gαq, the α-subunit of Gq protein, is ubiquitously expressed in mammalian cells. It initially attracted attention for its physiological significance in cardiovascular system. In recent years, studies have also indicated the important roles of Gαq in regulating immunity, supplying us a new insight into the mechanism of immune regulation. T helper type 17 (Th17) cells are potent inducers of tissue inflammation. Many studies have shown that Th17 cells are major effector cells in the pathogenesis of many experimental autoimmune diseases and human inflammatory conditions such as rheumatoid arthritis (RA). One of our previous studies has shown that Gαq negatively controls the disease activity of RA. However, how Gαq controls the pathogenesis of autoimmune disease is not clear. Whether this effect is via the regulation of Th17 differentiation is still not known. We aimed to find out the role of Gαq in control of Th17 differentiation. We investigated the relationship between Gαq and Th17 in RA patients. We then investigated the mechanism of how Gαq regulated Th17 differentiation by using Gnaq(-/-) mice. We observed that the expression of Gαq was negatively associated with interleukin-17A expression in RA patients, indicating that Gαq negatively controlled the differentiation of Th17 cells. By using Gnaq(-/-) mice, we demonstrated that Gαq inhibited the differentiation of Th17 cell via regulating the activity of extracellular signal-regulated kinase-1/2 to control the expression of STAT3 (signal transducer and activator of transcription 3) and RORα (RAR-related orphan receptor-α). These data suggest the possibility of targeting Gαq to develop a novel therapeutic regimen for autoimmune disease.
Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital, Xiamen University, Xiamen, China.
Yuan
Y
Liu
Molecular Biology Research Center, Shandong Medical College, Linyi, China.
Dashan
D
Wang
Department of Endocrinology and Metabolism, The Third People's Hospital of Chengdu and The Second Affiliated Clinical College of Chengdu of Chongqing Medical University, Chengdu, China.
Fang
F
Li
Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital, Xiamen University, Xiamen, China.
Guixiu
G
Shi
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D044385:GTP-Binding Protein alpha Subunits / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D005786:Gene Expression Regulation; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D038041:Lymphopoiesis / Q000235:genetics / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011828:Radiation Chimera; D050796:STAT3 Transcription Factor / Q000502:physiology; D013167:Spondylitis, Ankylosing / Q000235:genetics / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology*
D005419:Flavonoids; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; C508717:IL17A protein, human; D020381:Interleukin-17; D015850:Interleukin-6; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D012333:RNA, Messenger; C539739:Rora protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C577686:interleukin-6, mouse; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one