Fenofibrate Represses Interleukin-17 and Interferon-γ Expression and Improves Colitis in Interleukin-10–Deficient Mice

Lee, Jimmy W.; Bajwa, Poonam J.; Carson, Monica J.; Jeske, Daniel R.; Cong, Yingzi; Elson, Charles O.; Lytle, Christian; Straus, Daniel S.

doi:10.1053/j.gastro.2007.03.113

Cited by 120 publications

(130 citation statements)

References 70 publications

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“…In inflammatory bowel disease, the epithelial cells lining the lumen of the gastrointestinal tract are an important source of chemokines (13,30,31). We show here that IL-17 represses TNF-␣-elicited CXCL10 and 11 gene expression in HT-29 colonic epithelial cells.…”

Section: Differential Regulation Of Chemokines By Il-17 In Colonicmentioning

confidence: 57%

“…Although Th1-polarizing conditions inhibit induction of Th17 cells, in some contexts the two cell types seem to cooperate in initiating and/or perpetuating chronic inflammation. For example, in human inflammatory diseases including Crohn's disease (4) and psoriasis (6) and in the IL-10 knockout mouse model of inflammatory bowel disease (13), high levels of IFN-␥ and IL-17 may be found together in the same specimens of inflamed tissue. Further complicating the understanding of Th1-Th17 interaction, a newly identified subset of T cells termed Th1/ Th17 has been found to have features of both Th1 and Th17, including production of both IFN-␥ and IL17 (4,7,12,14).…”

Section: Differential Regulation Of Chemokines By Il-17 In Colonicmentioning

confidence: 99%

“…HT-29 CL19A human colorectal cancer cells were cultured in McCoy's 5A medium supplemented with 10% FBS, penicillin (100 U/ml), and streptomycin (100 g/ml) (13). CD4 ϩ human T cells enriched for IL-17-producing cells were prepared as described previously (37) with minor modifications.…”

Section: Cell Culturementioning

confidence: 99%

“…In all experiments, the plasmid pCMV-␤gal, in which the ␤-galactosidase gene is under control of the CMV enhancer plus promoter, was cotransfected along with the luciferase reporter as an internal control for transfection efficiency and for the specificity of the effects observed (13). To determine the effect of TNF-␣ and IL-17 on promoter activity, cells were transferred to medium with 0.5% serum for 14 h before cytokine addition.…”

Section: Promoter Activity Assaymentioning

confidence: 99%

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Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells

Lee

Wang

Kattah³

et al. 2008

The Journal of Immunology

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119

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The IL-23/IL-17 pathway plays an important role in chronic inflammatory diseases, including inflammatory bowel disease. In inflammatory bowel disease, intestinal epithelial cells are an important source of chemokines that recruit inflammatory cells. We examined the effect of IL-17 on chemokine expression of HT-29 colonic epithelial cells. IL-17 strongly repressed TNF-α-stimulated expression of CXCL10, CXCL11, and CCL5, but synergized with TNF-α for induction of CXCL8, CXCL1, and CCL20 mRNAs. For CXCL10, IL-17 strongly inhibited promoter activity but had no effect on mRNA stability. In contrast, for CXCL8, IL-17 slightly decreased promoter activity but stabilized its normally unstable mRNA, leading to a net increase in steady-state mRNA abundance. IL-17 synergized with TNF-α in transactivating the epidermal growth factor receptor (EGFR) and in activating ERK and p38 MAPK. The p38 and ERK pathway inhibitors SB203580 and U0126 reversed the repressive effect of IL-17 on CXCL10 mRNA abundance and promoter activity and also reversed the inductive effect of IL-17 on CXCL8 mRNA, indicating that MAPK signaling mediates both the transcriptional repression of CXCL10 and the stabilization of CXCL8 mRNA by IL-17. The EGFR kinase inhibitor AG1478 partially reversed the effects of IL-17 on CXCL8 and CXCL10 mRNA, demonstrating a role for EGFR in downstream IL-17 signaling. The overall results indicate a positive effect of IL-17 on chemokines that recruit neutrophils (CXCL8 and CXCL1), and Th17 cells (CCL20). In contrast, IL-17 represses expression of CXCL10, CXCL11, and CCR5, three chemokines that selectively recruit Th1 but not other effector T cells.

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Section: Differential Regulation Of Chemokines By Il-17 In Colonicmentioning

confidence: 57%

Section: Differential Regulation Of Chemokines By Il-17 In Colonicmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

Section: Promoter Activity Assaymentioning

confidence: 99%

See 2 more Smart Citations

Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells

Lee

Wang

Kattah³

et al. 2008

The Journal of Immunology

Self Cite

119

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“…These findings indicate the importance of PPARα in T cells as a negative regulator, especially in males. In colitis models, fenofibrate treatment inhibited IFN-γ and IL-17 production, as well as decreased disease severity in IL-10 -/-mice (Lee et al, 2007). The synthetic ligand WY-14643 also showed reduced inflammatory cytokine production and disease severity in the DSSinduced colitis model (Azuma et al, 2010), suggesting that this ligand is a potential therapeutic for treating autoimmune diseases.…”

Section: Ppars In T Cells and Autoimmunitymentioning

confidence: 97%

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

Choi¹,

Bothwell

2012

Molecules and Cells

149

111

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Members of the nuclear receptor superfamily function as transcription factors involved in innate and adaptive immunity as well as lipid metabolism. These highly conserved proteins participate in ligand-dependent or -independent regulatory mechanisms that affect gene expression. Peroxisome proliferator-activated receptors (PPARs), which include PPARα, PPARβ/δ, and PPARγ, are a group of nuclear receptor proteins that play diverse roles in cellular differentiation, development, and metabolism. Each PPAR subfamily is activated by different endogenous and synthetic ligands. Recent studies using specific ligand treatments and cell type-specific PPAR knockout mice have revealed important roles for these proteins in T-cell-related autoimmune diseases. Moreover, PPARs have been shown to regulate T-cell survival, activation, and CD4 + T helper cell differentiation into the Th1, Th2, Th17, and Treg lineages. Here, we review the studies that provide insight into the important regulatory roles of PPARs in T-cell activation, survival, proliferation, differentiation, and autoimmune disease.

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Fibrates ameliorate the course of bacterial sepsis by promoting neutrophil recruitment via CXCR2

et al. 2014

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Bacterial sepsis results in high mortality rates, and new therapeutics to control infection are urgently needed. Here, we investigate the therapeutic potential of fibrates in the treatment of bacterial sepsis and examine their effects on innate immunity. Fibrates significantly improved the survival from sepsis in mice infected with Salmonella typhimurium, which was paralleled by markedly increased neutrophil influx to the site of infection resulting in rapid clearance of invading bacteria. As a consequence of fibrate-mediated early control of infection, the systemic inflammatory response was repressed in fibrate-treated mice. Mechanistically, we found that fibrates preserve chemotaxis of murine neutrophils by blocking LPS-induced phosphorylation of ERK. This results in a decrease of G protein-coupled receptor kinase-2 expression, thereby inhibiting the LPS-mediated downregulation of CXCR2, a chemokine receptor critical for neutrophil recruitment. Accordingly, application of a synthetic CXCR2 inhibitor completely abrogated the protective effects of fibrates in septicemia in vivo. Our results unravel a novel function of fibrates in innate immunity and host response to infection and suggest fibrates as a promising adjunct therapy in bacterial sepsis.

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Fenofibrate Represses Interleukin-17 and Interferon-γ Expression and Improves Colitis in Interleukin-10–Deficient Mice

Cited by 120 publications

References 70 publications

Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells

Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

Fibrates ameliorate the course of bacterial sepsis by promoting neutrophil recruitment via CXCR2

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