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IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor.

ABSTRACT: The T helper 17 (Th17) cell lineage is important in inflammatory and autoimmune responses, via its ability to produce interleukin-17 (IL-17) and IL-21. Given the potentially deleterious effects of Th17 cells, their generation needs to be strictly controlled. IRF-4 is a transcription factor that has recently emerged as a key regulator of Th17 cell differentiation. Here, we showed that mice deficient in a previously isolated protein, IBP (IRF-4-binding protein), rapidly developed rheumatoid arthritis-like joint disease and large-vessel vasculitis. The pathology was associated with an enhanced responsiveness of T cells to low levels of stimulation and with the inappropriate synthesis of IL-17 and IL-21. IBP sequestered IRF-4 and prevented it from targeting the transcriptional regulatory regions of the genes that encode IL-17 and IL-21. Thus, IBP appears to be important in preventing T cell-mediated autoimmunity by ensuring that the production of IL-17 and IL-21 does not occur in response to self-antigens.

SUBMITTER: Chen Q

PROVIDER: S-EPMC2633410 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor.

Chen Qinzhong Q Yang Wen W Gupta Sanjay S Biswas Partha P Smith Paula P Bhagat Govind G Pernis Alessandra B AB

Immunity 20081208 6

The T helper 17 (Th17) cell lineage is important in inflammatory and autoimmune responses, via its ability to produce interleukin-17 (IL-17) and IL-21. Given the potentially deleterious effects of Th17 cells, their generation needs to be strictly controlled. IRF-4 is a transcription factor that has recently emerged as a key regulator of Th17 cell differentiation. Here, we showed that mice deficient in a previously isolated protein, IBP (IRF-4-binding protein), rapidly developed rheumatoid arthri ...[more]

PMID: 19062315

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Project description:The expression of granulocyte colony-stimulating factor (G-CSF), the major regulator of neutrophil maturation, by human fibroblast-like synoviocytes (FLS) can be stimulated by the inflammatory cytokine interleukin-1β (IL-1β). G-CSF is known to contribute to the pathologic processes of destructive arthritis, but the induction mechanism remains unknown. The aims of this study were to identify the signaling pathways involved in IL-1β-stimulated G-CSF production and to determine whether this process was inhibited by aciculatin (8-((2R,4S,5S,6R)-tetrahydro-4,5-dihydroxy-6-methyl-2H-pyran-2-yl)-5-hydroxy-2-(4-hydroxyphenyl)-7-methoxy-4H-chromen-4-one), the major bioactive component of Chrysopogon aciculatus. IL-1β-induced cytokine expression was evaluated by measuring mRNA and protein levels by RT-PCR, ELISA, and Milliplex® assay. Whether aciculatin inhibited IL-1β-stimulated G-CSF expression, and if so, how, were evaluated using western blot assay, an electrophoretic mobility shift assay, and a reporter gene assay. Neutrophil differentiation was determined by Wright-Giemsa staining and flow cytometry. Aciculatin markedly inhibited G-CSF expression induced by IL-1β (10 ng/mL) in a concentration-dependent manner (1-10 µM). In clarifying the mechanisms involved, aciculatin was found to inhibit the IL-1β-induced activation of the IκB kinase (IKK)/IκB/nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways by suppressing the DNA binding activity of the transcription factors NF-κB and activator protein (AP)-1. Furthermore, aciculatin significantly inhibited the G-CSF-mediated phosphorylation of Janus kinase-signal transducer and activator of transcription (JAK-STAT) and Akt and neutrophil differentiation from precursor cells. Our results show that aciculatin inhibits IL-1β-stimulated G-CSF expression and the subsequent neutrophil differentiation, suggesting that it might have therapeutic potential for inflammatory arthritis.

Dataset Information

IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor.

Publications

IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor.

Similar Datasets

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