title: Adenosine signaling inhibits CIITA-mediated MHC class II transactivation in lung fibroblast cells.
abstract: Efficient antigen presentation by major histocompatibility complex (MHC) molecules represents a critical process in adaptive immunity. Class II transactivator (CIITA) is considered the master regulator of MHC class II (MHC II) transcription. Previously, we have shown that CIITA expression is upregulated in smooth muscle cells deficient in A2b adenosine receptor. Here, we report that treatment with the adenosine receptor agonist adenosine-5'N-ethylcarboxamide (NECA) attenuated MHC II transcription in lung fibro-blast cells as a result of CIITA repression. Further analysis revealed that NECA preferentially abrogated CIITA transcription through promoters III and IV. Blockade with a selective A2b receptor antagonist MRS-1754 restored CIITA-dependent MHC II transactivation. Forskolin, an adenylyl cyclase activator, achieved the same effect as NECA. A2b signaling repressed CIITA transcription by altering histone modifications and recruitment of key factors on the CIITA promoters in a STAT1-dependent manner. MRS-1754 blocked the antagonism of transforming growth factor beta (TGF-β) in CIITA induction by interferon gamma (IFN-γ), alluding to a potential dialogue between TGF-β and adenosine signaling pathways. Finally, A2b signaling attenuated STAT1 phosphorylation and stimulated TGF-β synthesis. In conclusion, we have identified an adenosine-A2b receptor-adenylyl cyclase axis that influences CIITA-mediated MHC II transactivation in lung fibroblast cells and as such have provided invaluable insights into the development of novel immune-modulatory strategies.
authors.affiliation: Department of Surgery, Jiangsu Jiankang Vocational College, Nanjing, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.forename: Jun
authors.initials: J
authors.lastname: Xia
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
authors.forename: Hui
authors.initials: H
authors.lastname: Kong
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Weiping
authors.initials: W
authors.lastname: Xie
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D017951:Antigen Presentation; D000970:Antineoplastic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000081:Acetamides; D058917:Adenosine A2 Receptor Antagonists; D000970:Antineoplastic Agents; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; C423842:N-(4-cyanophenyl)-2-(4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy)acetamide; D009687:Nuclear Proteins; D058906:Purinergic P1 Receptor Agonists; D011687:Purines; D043704:Receptor, Adenosine A2B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D005576:Colforsin; D019830:Adenosine-5'-(N-ethylcarboxamide); D007371:Interferon-gamma
keywords: Adenosine A2b signaling; CIITA; Epigenetics; MHC class II; Transcriptional regulation