title: AP-1 is involved in ICOS gene expression downstream of TCR/CD28 and cytokine receptor signaling.
abstract: It has been proposed that sustained ICOS expression in chronic inflammatory immune conditions, such as autoimmunity and allergy, contributes to symptom exacerbation. Therefore modulation of ICOS gene expression could be a potential therapeutic strategy for such immune diseases. However, the precise molecular mechanisms controlling ICOS gene expression remain poorly understood. In this study, we explored transcription factors involving in ICOS gene expression and examined their roles in a physiological situation. Microarray analysis revealed that one AP-1 molecule, Fos-related antigen-2 (Fra2), was highly correlated with ICOS expression. Ectopic expression of Fra2 and other AP-1 molecules upregulated ICOS expression on T cells. We identified an AP-1-responsive site (AP1-RE) within the ICOS promoter region and demonstrated AP-1 actually binds to AP1-RE upon TCR/CD28 stimulation. Meanwhile, we found several cytokines could upregulate ICOS expression on both naïve and effector T cells in a manner independent of TCR/CD28 stimulation. These cytokine stimuli induced AP-1 binding to AP1-RE. Together, our results indicate AP-1 transcription factors are involved in ICOS gene expression downstream of both TCR/CD28 signaling and cytokine receptor signaling, and suggest AP-1 activation via cytokine receptor signaling may be one of the mechanisms maintaining high level ICOS expression in chronic inflammatory immune responses.
authors.affiliation: Research Institute for Biological Sciences, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Watanabe
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Nakajima
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Ohnuki
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ogawa
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Yamashita
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Murakami
authors.forename: Kazunari
authors.initials: K
authors.lastname: Tanabe
authors.forename: Ryo
authors.initials: R
authors.lastname: Abe
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D051921:Fos-Related Antigen-2 / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D018121:Receptors, Cytokine / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000276:immunology*
chemical_list: D018106:CD28 Antigens; D051921:Fos-Related Antigen-2; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D018121:Receptors, Cytokine; D018808:Transcription Factor AP-1