PMID:22585681

Citation	Watanabe, M, Nakajima, S, Ohnuki, K, Ogawa, S, Yamashita, M, Nakayama, T, Murakami, Y, Tanabe, K and Abe, R (2012) AP-1 is involved in ICOS gene expression downstream of TCR/CD28 and cytokine receptor signaling. Eur. J. Immunol. 42:1850-62
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.
Links	PubMed Online version:10.1002/eji.201141897
Keywords	Animals; Antigens, CD28/immunology; Antigens, CD28/metabolism; Autoimmunity/immunology; CD4-Positive T-Lymphocytes/immunology; Flow Cytometry; Fos-Related Antigen-2/genetics; Fos-Related Antigen-2/immunology; Gene Expression Regulation/immunology; Inducible T-Cell Co-Stimulator Protein/biosynthesis; Inducible T-Cell Co-Stimulator Protein/genetics; Inducible T-Cell Co-Stimulator Protein/immunology; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; RNA, Messenger/chemistry; RNA, Messenger/genetics; Receptors, Antigen, T-Cell/immunology; Receptors, Antigen, T-Cell/metabolism; Receptors, Cytokine/immunology; Receptors, Cytokine/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Specific Pathogen-Free Organisms; Transcription Factor AP-1/genetics; Transcription Factor AP-1/immunology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:FOSL2		GO:0045893: positive regulation of transcription, DNA-dependent	ECO:0000314:		P		Figure 2A, shows that over a 36 hour period, FRA-2 causes greater than a 10 fold increase in ICOS mRNA levels, within mouse splenic CD4+ T cells.	complete CACAO 7593
MOUSE:FOSL2	involved_in	GO:0045893: positive regulation of transcription, DNA-templated	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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