title: Calcitonin gene-related peptide and cyclic adenosine 5'-monophosphate/protein kinase A pathway promote IL-9 production in Th9 differentiation process.
abstract: Th9 cells are a novel Th cell subset that produces IL-9 and is involved in type I hypersensitivity such as airway inflammation. Although its critical roles in asthma have attracted interest, the physiological regulatory mechanisms of Th9 cell differentiation and function are largely unknown. Asthma is easily affected by psychological factors. Therefore, we investigated one of the physiological mediators derived from the nervous system, calcitonin gene-related peptide (CGRP), in asthma and Th9 cells because CGRP and activation of the cAMP/protein kinase A (PKA) pathway by CGRP are known to be important regulators in several immune responses and allergic diseases. In this study, we demonstrated that the CGRP/cAMP/PKA pathway promotes IL-9 production via NFATc2 activation by PKA-dependent glycogen synthase kinase-3β inactivation. Moreover, CGRP also induces the expression of PU.1, a critical transcriptional factor in Th9 cells, which depends on PKA, but not NFATc2. Additionally, we demonstrated the physiological importance of CGRP in IL-9 production and Th9 differentiation using an OVA-induced airway inflammation model and T cell-specific CGRP receptor-deficient mice. The present study revealed a novel regulatory mechanism comprising G protein-coupled receptor ligands and nervous system-derived substances in Th9 cell differentiation and type I hypersensitivity.
authors.affiliation: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Mikami
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Miyagi
authors.forename: Kaori
authors.initials: K
authors.lastname: Sueda
authors.forename: Miku
authors.initials: M
authors.lastname: Takatsuji
authors.forename: So-ichiro
authors.initials: S
authors.lastname: Fukada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Kazutake
authors.initials: K
authors.lastname: Tsujikawa
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000502:physiology*; D002454:Cell Differentiation / Q000276:immunology*; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism
chemical_list: C569167:IL1F9 protein, mouse; D007375:Interleukin-1; D000242:Cyclic AMP; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D015740:Calcitonin Gene-Related Peptide