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Identification of human thioredoxin as a novel IFN-gamma-induced factor: mechanism of induction and its role in cytokine production.

ABSTRACT: IFN-gamma is a multifunctional peptide with a potent immune defense function which is also known as a prototypic Th1 cytokine. While screening for genes differentially expressed by Th1 and Th2 cytokines, human thioredoxin was identified as a novel target gene induced by IFN-gamma. The mechanism by which thioredoxin is induced by IFN-gamma and the signaling pathways involved in its induction were analyzed. In addition, the effects of thioredoxin on immune cell survival and cytokine production were examined by thioredoxin over-expression and recombinant thioredoxin treatment.Human thioredoxin was selectively induced by IFN-gamma in monocytic and T cell lines. In monocytic cells, the induction of thioredoxin gene expression by IFN-gamma was dose-dependent, and both the mRNA and protein levels were increased by 2~3 fold within 4 to 24 h hours of IFN-gamma treatment. The thioredoxin induction by IFN-gamma was insensitive to cycloheximide treatment, suggesting that it is a primary response gene induced by IFN-gamma. Subsequent analysis of the signaling pathways indicated that the Jak/Stat, Akt, and Erk pathways play a role in IFN-gamma signaling that leads to thioredoxin gene expression. Thioredoxin was induced by oxidative or radiation stresses, and it protected the immune cells from apoptosis by reducing the levels of reactive oxygen species. Furthermore, thioredoxin modulated the oxidant-induced cytokine balance toward Th1 by counter-regulating the production of IL-4 and IFN-gamma in T cells.These data suggest that thioredoxin is an IFN-gamma-induced factor that may play a role in developing Th1 immunity and in the maintenance of immune homeostasis upon infection, radiation, and oxidative stress.

SUBMITTER: Kim SH

PROVIDER: S-EPMC2596082 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Identification of human thioredoxin as a novel IFN-gamma-induced factor: mechanism of induction and its role in cytokine production.

Kim Seol-Hee SH Oh Jiyoung J Choi Ja-Young JY Jang Ji-Young JY Kang Myoung-Wha MW Lee Choong-Eun CE

BMC immunology 20081105

<h4>Background</h4>IFN-gamma is a multifunctional peptide with a potent immune defense function which is also known as a prototypic Th1 cytokine. While screening for genes differentially expressed by Th1 and Th2 cytokines, human thioredoxin was identified as a novel target gene induced by IFN-gamma. The mechanism by which thioredoxin is induced by IFN-gamma and the signaling pathways involved in its induction were analyzed. In addition, the effects of thioredoxin on immune cell survival and cyto ...[more]

PMID: 18983687

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Project description:IntroductionIFN-gamma inducible protein-10 (CXCL10), a member of the CXC chemokine family, and its receptor CXCR3 contribute to the recruitment of T cells from the blood stream into the inflamed joints and have a crucial role in perpetuating inflammation in rheumatoid arthritis (RA) synovial joints. Recently we showed the role of CXCL10 on receptor activator of nuclear factor kappa-B ligand (RANKL) expression in an animal model of RA and suggested the contribution to osteoclastogenesis. We tested the effects of CXCL10 on the expression of RANKL in RA synoviocytes and T cells, and we investigated which subunit of CXCR3 contributes to RANKL expression by CXCL10.MethodsSynoviocytes derived from RA patients were kept in culture for 24 hours in the presence or absence of TNF-α. CXCL10 expression was measured by reverse transcriptase polymerase chain reaction (RT-PCR) of cultured synoviocytes. Expression of RANKL was measured by RT-PCR and western blot in cultured synoviocytes with or without CXCL10 and also measured in Jurkat/Hut 78 T cells and CD4+ T cells in the presence of CXCL10 or dexamethasone. CXCL10 induced RANKL expression in Jurkat T cells was tested upon the pertussis toxin (PTX), an inhibitor of Gi subunit of G protein coupled receptor (GPCR). The synthetic siRNA for Gαi(2) was used to knock down gene expression of respective proteins.ResultsCXCL10 expression in RA synoviocytes was increased by TNF-α. CXCL10 slightly increased RANKL expression in RA synoviocytes, but markedly increased RANKL expression in Jurkat/Hut 78 T cell or CD4+ T cell. CXCL10 augmented the expression of RANKL by 62.6%, and PTX inhibited both basal level of RANKL (from 37.4 ± 16.0 to 18.9 ± 13.0%) and CXCL10-induced RANKL expression in Jurkat T cells (from 100% to 48.6 ± 27.3%). Knock down of Gα(i2) by siRNA transfection, which suppressed the basal level of RANKL (from 61.8 ± 17.9% to 31.1 ± 15.9%) and CXCL10-induced RANKL expression (from 100% to 53.1 ± 27.1%) in Jurkat T cells, is consistent with PTX, which inhibited RANKL expression.ConclusionsCXCL10 increased RANKL expression in CD4+ T cells and it was mediated by Gα(i) subunits of CXCR3. These results indicate that CXCL10 may have a potential role in osteoclastogenesis of RA synovial tissue and subsequent joint erosion.

Dataset Information

Identification of human thioredoxin as a novel IFN-gamma-induced factor: mechanism of induction and its role in cytokine production.

Publications

Identification of human thioredoxin as a novel IFN-gamma-induced factor: mechanism of induction and its role in cytokine production.

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