Interleukin-6 Induces Expression of Ifi202, an Interferon-inducible Candidate Gene for Lupus Susceptibility

Pramanik, Rocky; Jørgensen, Trine N.; Hong, Xin; Kotzin, Brian L.; Choubey, Divaker

doi:10.1074/jbc.m313140200

Cited by 46 publications

(42 citation statements)

References 48 publications

(66 reference statements)

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“…It is noteworthy that STAT3 activation is required for the suppression by IL-6 of LPS-dependent cell maturation. IL-6 also induces through STAT3 the Ifi202 gene and p202 protein in mouse splenocytes (50). These findings are proximately relevant to those reported here because Ifi202 represents a candidate susceptibility gene for autoimmune diseases such as lupus erythematosus.…”

Section: Discussionsupporting

confidence: 70%

IL-1β Induces IL-6 Expression in Human Orbital Fibroblasts: Identification of an Anatomic-Site Specific Phenotypic Attribute Relevant to Thyroid-Associated Ophthalmopathy

Chen

Tsui

Smith

2005

The Journal of Immunology

119

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Human orbital fibroblasts exhibit a unique inflammatory phenotype. In the present study, we report that these fibroblasts, when treated with IL-1β, express high levels of IL-6, a cytokine involved in B cell activation and the regulation of adipocyte metabolism. The magnitude of this induction is considerably greater than that in dermal fibroblasts and involves up-regulation of IL-6 mRNA levels. IL-1β activates both p38 and ERK 1/2 components of the MAPK pathways. Disrupting these could attenuate the IL-6 induction. The up-regulation involves enhanced IL-6 gene promoter activity and retardation of IL-6 mRNA decay by IL-1β. Dexamethasone completely blocked the effect of IL-1β on IL-6 expression. Orbital fibroblasts also express higher levels of IL-6R than do skin-derived cells. When treated with rIL-6 (10 ng/ml), STAT3 is transiently phosphorylated. Thus, the exaggerated capacity of orbital fibroblasts to express high levels of both IL-6 and its receptor in an anatomic site-selective manner could represent an important basis for immune responses localized to the orbit in Graves’ disease.

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Section: Discussionsupporting

confidence: 70%

IL-1β Induces IL-6 Expression in Human Orbital Fibroblasts: Identification of an Anatomic-Site Specific Phenotypic Attribute Relevant to Thyroid-Associated Ophthalmopathy

Chen

Tsui

Smith

2005

The Journal of Immunology

119

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“…Wang et al 34 and Trapani et al, 35 and our unpublished data), and the proinflammatory cytokine interleukin-6. 16 Analyses of basal Ifi202 levels in total splenocytes from IFNAR þ / þ , IFNAR þ /À and IFNAR À/À B6.Nba2 mice showed that levels were reduced in mice in which IFNab signaling was abolished. Also, as expected, Ifi202 failed to get upregulated in IFNAR-deficient splenocytes after exposure to IFNabs in vitro.…”

Section: Discussionmentioning

confidence: 99%

Type I interferon signaling is involved in the spontaneous development of lupus-like disease in B6.Nba2 and (B6.Nba2 × NZW)F1 mice

et al. 2007

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Several studies have described a role for type I interferons (IFNab) in the initiation and/or prolongation of autoimmune diseases. Most pronounced has been the association of disease activity with what is now known as 'the interferon signature' of gene expression in peripheral blood mononuclear cells from lupus patients. In correlation, studies have shown that inhibition of IFNab signaling abrogates disease in various mouse models of lupus. New Zealand black (NZB) and B6.Nba2 congenic mice spontaneously develop elevated levels of serum anti-nuclear autoantibodies (ANAs). Nevertheless, neither of these strains develop fatal renal disease. The female F1 offspring of NZB or B6.Nba2 crossed with New Zealand white (NZW) mice do, however, develop kidney disease. We have previously shown that increases in endogenous IFNab levels in (B6.Nba2 Â NZW)F1 mice leads to accelerated development of renal disease in an IFNab-dependent manner. We now show that B6.Nba2 and (B6.Nba2 Â NZW)F1 mice deficient for the IFNab-receptor fail to develop ANA and renal disease, although the mice have substantial immune complex deposition in the glomeruli. Thus, endogenous IFNab might influence disease by affecting B-cell activation and differentiation, as well as the kidneys' susceptibility to damage, the latter perhaps through induction of a local inflammatory milieu.

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“…The protein p202 (52 kDa) is an inducible transcriptional modulator (13,(15)(16)(17) that belongs to the p200 protein family (18). The family includes structurally related mouse proteins, such as p202 (both p202a and p202b (13)), p203, and p204 (18,19).…”

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

“…Isolated total RNA (1 g) was subjected to cDNA synthesis using SuperScript First-Stand Synthesis system (Invitrogen Life Technologies), as suggested by the supplier, followed by PCR, using a pair of primers specific to the Ifi202a (forward primer, 5Ј-ggtcatctaccaactcagaat-3Ј; reverse primer, 5Ј-ctctaggatgccactgctgttg-3Ј), as described previously (17). Primer sequences for other genes are available upon request.…”

Section: Rt-pcrmentioning

confidence: 99%

Increased Expression of Ifi202, an IFN-Activatable Gene, in B6.Nba2 Lupus Susceptible Mice Inhibits p53-Mediated Apoptosis

Hong

D’Souza

Jørgensen

et al. 2006

The Journal of Immunology

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Increased expression of p202 protein (encoded by the Ifi202 gene) in splenocytes derived from B6.Nba2 mice (congenic for the Nba2 interval derived from the New Zealand Black mice) was correlated with defects in apoptosis of splenic B cells and increased susceptibility to develop systemic lupus erythematosus. We have now investigated the molecular mechanisms by which increased expression of p202 in B6.Nba2 cells contributes to defects in apoptosis. In this study, we report that increased expression of p202 in the B6.Nba2 splenocytes, as compared with cells derived from the parental C57BL/6 (B6) mice, was correlated with increased levels of p53 protein and inhibition of p53-mediated transcription of target genes that encode proapoptotic proteins. Conversely, knockdown of p202 expression in B6.Nba2 cells resulted in stimulation of p53-mediated transcription. We found that p202 bound to p53 in the N-terminal region (aa 44–83) comprising the proline-rich region that is important for p53-mediated apoptosis. Consistent with the binding of p202 to p53, increased expression of p202 in B6.Nba2 mouse embryonic fibroblasts inhibited UV-induced apoptosis. Taken together, our observations support the idea that increased expression of p202 in B6.Nba2 mice increases the susceptibility to develop lupus, in part, by inhibiting p53-mediated apoptosis.

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Interleukin-6 Induces Expression of Ifi202, an Interferon-inducible Candidate Gene for Lupus Susceptibility

Cited by 46 publications

References 48 publications

IL-1β Induces IL-6 Expression in Human Orbital Fibroblasts: Identification of an Anatomic-Site Specific Phenotypic Attribute Relevant to Thyroid-Associated Ophthalmopathy

IL-1β Induces IL-6 Expression in Human Orbital Fibroblasts: Identification of an Anatomic-Site Specific Phenotypic Attribute Relevant to Thyroid-Associated Ophthalmopathy

Type I interferon signaling is involved in the spontaneous development of lupus-like disease in B6.Nba2 and (B6.Nba2 × NZW)F1 mice

Increased Expression of Ifi202, an IFN-Activatable Gene, in B6.Nba2 Lupus Susceptible Mice Inhibits p53-Mediated Apoptosis

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