title: Anti-inflammatory or proinflammatory effect of an adenosine receptor agonist on the Th17 autoimmune response is inflammatory environment-dependent.
abstract: Adenosine is a key endogenous signaling molecule that regulates a wide range of physiological functions, including immune system function and inflammation. Studies have shown that adenosine receptor (AR) agonists can be either anti-inflammatory or proinflammatory in immune responses and in inflammation, and the clarification of the mechanisms causing these opposing effects should provide a better guide for therapeutic intervention. Whereas previous studies mostly examined the effects of AR agonists on Th1-type immune responses, in this study, we compared their effect on Th17 and Th1 autoimmune responses in experimental autoimmune uveitis, a mouse model of human uveitis induced by immunization with the human interphotoreceptor retinoid-binding protein peptides 1-20. We showed that injection of mice with a nonselective AR agonist, 5'-N-ethylcarboxamidoadenosine (NECA), at an early stage after immunization had an inhibitory effect on both Th1 and Th17 responses, whereas injection of the same amount of NECA at a late stage inhibited the Th1 response but had an enhancing effect on the Th17 response. We also showed that the effects of NECA on Th1 and Th17 responses were completely dissociated, that the enhancing effect of NECA on Th17 responses was modulated by γδ T cells, and that the response of γδ T cells to NECA was determined by their activation status. We conclude that the inflammatory environment has a strong impact on converting the effect of AR agonist on the Th17 autoimmune response from anti-inflammatory to proinflammatory. Our observation should help in the designing of better AR-targeted therapies.
authors.affiliation: Doheny Eye Institute, University of California, Los Angeles, Los Angeles, CA 90033; Department of Ophthalmology, University of California, Los Angeles, Los Angeles, CA 90033; and.
authors.forename: Dongchun
authors.initials: D
authors.lastname: Liang
authors.affiliation: Doheny Eye Institute, University of California, Los Angeles, Los Angeles, CA 90033; Department of Ophthalmology, University of California, Los Angeles, Los Angeles, CA 90033; and.
authors.forename: Aijun
authors.initials: A
authors.lastname: Zuo
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, Louisville, KY 40202.
authors.forename: Hui
authors.initials: H
authors.lastname: Shao
authors.affiliation: Doheny Eye Institute, University of California, Los Angeles, Los Angeles, CA 90033; Department of Ophthalmology, University of California, Los Angeles, Los Angeles, CA 90033; and.
authors.forename: Mingjiazi
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, Louisville, KY 40202.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Kaplan
authors.affiliation: Doheny Eye Institute, University of California, Los Angeles, Los Angeles, CA 90033; Department of Ophthalmology, University of California, Los Angeles, Los Angeles, CA 90033; and dliang@doheny.org.
authors.forename: Deming
authors.initials: D
authors.lastname: Sun
mesh_terms: D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000008:administration & dosage*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology* / Q000628:therapy; D002478:Cells, Cultured; D005136:Eye Proteins / Q000276:immunology; D005260:Female; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects / Q000235:genetics; D018836:Inflammation Mediators / Q000008:administration & dosage*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D010446:Peptide Fragments / Q000276:immunology; D058906:Purinergic P1 Receptor Agonists / Q000008:administration & dosage*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000378:metabolism*; D012177:Retinol-Binding Proteins / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology*; D014605:Uveitis / Q000139:chemically induced / Q000276:immunology* / Q000628:therapy; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D019830:Adenosine-5'-(N-ethylcarboxamide); D000893:Anti-Inflammatory Agents; D001324:Autoantigens; D005136:Eye Proteins; D018836:Inflammation Mediators; D010446:Peptide Fragments; D058906:Purinergic P1 Receptor Agonists; D016692:Receptors, Antigen, T-Cell, gamma-delta; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial