Stromal cell‐derived factor‐1/CXCR4 promotes IL‐6 production in human synovial fibroblasts

Chen, Hsien‐Te; Tsou, Hsi‐Kai; Hsu, Chin‐Jung; Tsai, Chun‐Hao; Kao, Cheng-Hsing; Fong, Yi‐Chin; Tang, Chih-Hsin

doi:10.1002/jcb.23043

Cited by 35 publications

(26 citation statements)

References 26 publications

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“…34 Our preliminary analysis using the SABiosciences’ Text Mining Application and the UCSC Genome Browser revealed putative AP-1/c-Jun binding sites in the promoter region of the human IRAK-M gene.…”

Section: Resultsmentioning

confidence: 95%

IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor–associated kinase M

Wu¹,

Jiang²,

Smith³

et al. 2012

Journal of Allergy and Clinical Immunology

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Background Impaired airway mucosal immunity can contribute to increased respiratory tract infections in asthmatic patients, but the involved molecular mechanisms have not been fully clarified. Airway epithelial cells serve as the first line of respiratory mucosal defense to eliminate inhaled pathogens through various mechanisms, including Toll-like receptor (TLR) pathways. Our previous studies suggest that impaired TLR2 function in TH2 cytokine–exposed airways might decrease immune responses to pathogens and subsequently exacerbate allergic inflammation. IL-1 receptor–associated kinase M (IRAK-M) negatively regulates TLR signaling. However, IRAK-M expression in airway epithelium from asthmatic patients and its functions under a TH2 cytokine milieu remain unclear. Objectives We sought to evaluate the role of IRAK-M in IL-13–inhibited TLR2 signaling in human airway epithelial cells. Methods: We examined IRAK-M protein expression in epithelia from asthmatic patients versus that in normal airway epithelia. Moreover, IRAK-M regulation and function in modulating innate immunity (eg, TLR2 signaling) were investigated in cultured human airway epithelial cells with or without IL-13 stimulation. Results IRAK-M protein levels were increased in asthmatic airway epithelium. Furthermore, in primary human airway epithelial cells, IL-13 consistently upregulated IRAK-M expression, largely through activation of phosphoinositide 3-kinase pathway. Specifically, phosphoinositide 3-kinase activation led to c-Jun binding to human IRAK-M gene promoter and IRAK-M upregulation. Functionally, IL-13–induced IRAK-M suppressed airway epithelial TLR2 signaling activation (eg, TLR2 and human β-defensin 2), partly through inhibiting activation of nuclear factor κB. Conclusions Our data indicate that epithelial IRAK-M overexpression in TH2 cytokine–exposed airways inhibits TLR2 signaling, providing a novel mechanism for the increased susceptibility of infections in asthmatic patients.

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Section: Resultsmentioning

confidence: 95%

IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor–associated kinase M

Wu¹,

Jiang²,

Smith³

et al. 2012

Journal of Allergy and Clinical Immunology

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“…To elucidate the molecular mechanisms underlying IL-6 over-production in OA, several studies have investigated the factors upstream of IL-6, including adiponectin20, CCN421, SDF-1/CXCR422, leptin23, cyclin-dependent kinase inhibitor24 and CTGF25. Moreover, several consensus sequences for the binding of NF-κB, CREB, NF-IL-6, and AP-1 in the promoter of the IL-6, have been identified, which are able to induce IL-6 expression in response to various exogeneous stimuli2627.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic modifications of interleukin-6 in synovial fibroblasts from osteoarthritis patients

Yang

Zhou

Wang

et al. 2017

Sci Rep

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Osteoarthritis (OA) is the most common degenerative disease of the synovial joint. The synovial membrane is responsible for the inflammatory reaction leading to the secretion of macrophage-derived pro-inflammatory cytokines, such as IL-6. Suppressing IL-6 over-expression in synovial fibroblasts (SF) is a promising method to prevent OA development and progression, in which the prerequisite is the elucidation of the molecular mechanisms underlying IL-6 over-expression in SF. Currently, there are few reports concerning epigenetic modifications in IL-6 in OA SF. In the present study, we attempted to investigate this phenomenon. SF over-expressing IL-6 was collected from OA patients. DNA hypomethylation and histone hyperacetylation were observed in the IL-6 promoter regions in OA SF compared with normal SF. No differences in the status of H3K9 di-methylation, H3K27 tri-methylation and H3K4 tri-methylation were observed in the IL-6 promoter regions between normal and OA SF. DNA (cytosine-5-)-methyltransferase 3 alpha (Dnmt3a) overexpression and anacardic acid (histone acetyltransferase inhibitor) treatment increased DNA methylation and decreased histone acetylation in the IL-6 promoter, and IL-6 over-expression in OA SF was suppressed. These observations provide deeper insight into the pathogenesis of OA and can be used to design new drugs and develop new therapeutic methods to treat OA.

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“…In the knee, SDF-1 is produced by the synovium and secreted into the joint cavity and blood, however, its receptor CXCR4 is expressed on chondrocytes in the joint. Once SDF-1 binds to CXCR4 it activates extracellular signal-regulated enzyme (Erk) and associated kinase (p38 MAP kinase) signaling pathways and induces chondrocytes to release matrix metalloproteinases–the main enzymes that degrade cartilage matrix and that drive the pathogenesis of OA[18,19]. …”

Section: Discussionmentioning

confidence: 99%

T140 blocks the SDF-1/CXCR4 signaling pathway and prevents cartilage degeneration in an osteoarthritis disease model

et al. 2017

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Osteoarthritis (OA) is one of the most common diseases affecting older people; however, there remains no effective targeted drug to combat OA. The aims of this study were (1) to explore the effect of T140 in regulating degeneration of articular cartilage in vivo by targeted blocking of the SDF-1/CXCR4 signaling pathway, and (2) to provide experimental evidence for the development of a novel OA-targeted pharmacotherapy. Thirty-six healthy Hartley guinea pigs were randomly divided into three groups: a T140-treated group (n = 12), a phosphate buffer saline control group (n = 12) and an untreated control group (n = 12). At 2, 4, 6, 8, 10 and 12 weeks of treatment, SDF-1 in serum was quantified by enzyme-linked immunosorbent assay. At 12 weeks of treatment, the cartilage from knee tibial plateau in the knee joint was collected for H&E, Safranin-O staining and Mankin grading; measurement for mRNA levels of matrix metalloproteinases (MMP-3, MMP-9 and MMP-13), aggrecan (ACAN) and collagen II (Col II) using RT-PCR; and measurement for Col II protein levels by western blot. Results showed that SDF-1 in serum increased in the T140 group and increased in the control groups. H&E and Safranin-O staining revealed less cartilage loss in T140-treated animals compared to controls. The mRNA levels of MMP-3, MMP-9 and MMP-13 in cartilage were much lower in the T140 group than other groups, but mRNA levels of ACAN and Col II in cartilage were higher in the T140-treated group. Col II protein levels in the T140 group and control groups were different. T140 can downregulate the expression of matrix-degrading enzyme and lessen the degeneration of cartilage by blocking the SDF-1/CRCR4 signaling pathway in vivo. This mechanism may present a pharmacological target for the treatment of OA.

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Stromal cell‐derived factor‐1/CXCR4 promotes IL‐6 production in human synovial fibroblasts

Cited by 35 publications

References 26 publications

IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor–associated kinase M

IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor–associated kinase M

Epigenetic modifications of interleukin-6 in synovial fibroblasts from osteoarthritis patients

T140 blocks the SDF-1/CXCR4 signaling pathway and prevents cartilage degeneration in an osteoarthritis disease model

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