CXCL1 contributes to IL-6 expression in osteoarthritis and rheumatoid arthritis synovial fibroblasts by CXCR2, c-Raf, MA
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RESEARCH ARTICLE
Open Access
CXCL1 contributes to IL-6 expression in osteoarthritis and rheumatoid arthritis synovial fibroblasts by CXCR2, c-Raf, MAPK, and AP-1 pathway Sheng-Mou Hou1, Po-Chun Chen2,3,4, Chieh-Mo Lin5,6,7, Mei-Ling Fang8,9, Miao-Ching Chi10,11,12* and Ju-Fang Liu13*
Abstract Background: Osteoarthritis (OA) and rheumatoid arthritis (RA) are common joint disorders that are considered to be different diseases due to their unique molecular mechanisms and pathogenesis. Chemokines and their corresponding receptors have been well characterized in RA progression, but less so in OA pathogenesis. Methods: The human primary synovial fibroblasts (SFs) were obtained from human OA and RA tissue samples. The Western blot and qPCR were performed to analyze the expression levels of CXCL1, as well as CXCL-promoted IL-6 expression in both OASFs and RASFs. The signal cascades that mediate the CXCL1-promoted IL-6 expression were identified by using chemical inhibitors, siRNAs, and shRNAs. Results: Here, we found that both diseases feature elevated levels of CXCL1 and interleukin (IL)-6, an important proinflammatory cytokine that participates in OA and RA pathogenesis. In OASFs and RASFs, CXCL1 promoted IL-6 expression in a dose- and time-dependent manner. In OASFs and RASFs overexpressing CXCL1 or transduced with shRNA plasmid, IL-6 expression was markedly upregulated. CXCR2, c-Raf, and MAPKs were found to regulate CXCL1induced IL-6 expression in OASFs and RASFs. Finally, CXCL1 triggered the transcriptional activities of c-Jun (which regulates the expression of proinflammatory proteins) in OASFs and RASFs. Conclusions: Our present work suggests that the CXCL1/CXCR2 axis helps to orchestrate inflammatory responses in OA and RA SFs. Keywords: CXCL1, Osteoarthritis, Rheumatoid arthritis, IL-6
Introduction Chemokines and chemokine receptors are critical players in the disease processes of two inflammatory joint diseases: rheumatoid arthritis (RA) and osteoarthritis (OA) [1]. Chemokines are abundant in RA synovial fluid, while OA synovial fluid also reveals the presence of chondrocytes, * Correspondence: [email protected]; [email protected] 10 Chronic Disease and Health Promotion Research Center, Chang Gung University of Science and Technology, Puzi City 613, Chiayi County, Taiwan 13 School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, No. 250 Wu-Hsing Street, Taipei 110, Taiwan Full list of author information is available at the end of the article
synovial cells, and other cells capable of both expressing and responding to chemokines [2–4]. Both diseases are characterized by the extravasation of leukocytes from the vascular endothelium into the synovial tissue, a process that involves numerous chemokines and their receptors acting as synovial chemotactic mediators [5]. Chemokines are well recognized for their ability to recruit different leukocytes [6] and for their involvement in the migration of circulating cells into or within tissue [7, 8]. Chemokines have been classified by struc
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