title: Interleukin-6 enhances acid-induced apoptosis via upregulating acid-sensing ion channel 1a expression and function in rat articular chondrocytes.
abstract: The inflammatory cytokine interleukin-6 (IL-6) is a causative agent of rheumatoid arthritis (RA), a chronic inflammatory disease complicated with degenerative arthritic cartilage. However, the precise mechanism of IL-6 on chondrocyte apoptosis is largely unclear. Acid-sensing ion channels (ASICs), a family of extracellular H(+)-activated cation channels, can be transiently activated by extracellular acid and play a pivotal role in acid-induced cell injury. In the present study, to investigate the role of IL-6 in regulating acid-induced articular chondrocyte apoptosis, primary rat articular chondrocytes were subjected to different treatments with or without IL-6 in the presence of acid. The results showed that the mRNA and protein expressions of ASIC1a were significantly increased in articular cartilage and chondrocytes of adjuvant arthritis (AA) rats. IL-6 could dramatically upregulate the level of ASIC1a in a time- and dose-dependent manner, and induce the activation of JAK2, STAT3, ERK, JNK and NF-κB in articular chondrocytes. Moreover, both the respective inhibitors of these signaling pathways and the specific antibody against IL-6 receptor (tocilizumab) could partially abrogate the ASIC1a upregulation induced by IL-6. Furthermore, IL-6 inhibited the cell viability and enhanced LDH release, [Ca(2+)]i elevation, and apoptosis in acid-induced articular chondrocytes, and these changes could be reversed by using psalmotoxin 1(PcTX1), which is the specific antagonist of ASIC1a. In addition, pretreatment with PcTX1 could inhibit the downregulated expression of Bcl-2 and the upregulated expression of Bax induced by IL-6 in acid-induced articular chondrocytes. Taken together, these results indicated that IL-6 could enhance acid-induced articular chondrocyte apoptosis, the mechanism of which might partially be involved with its ability of regulating the activation of ASIC1a-dependent JAK2/STAT3 and MAPK/NF-κB signaling pathways.
authors.affiliation: Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.
authors.forename: Renpeng
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.
authors.forename: Zhisen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.
authors.forename: Jinfang
authors.initials: J
authors.lastname: Ge
authors.affiliation: Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China. Electronic address: cfhchina@sohu.com.
authors.forename: Feihu
authors.initials: F
authors.lastname: Chen
mesh_terms: D062565:Acid Sensing Ion Channels / Q000096:biosynthesis* / Q000187:drug effects; D000143:Acids; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D002358:Cartilage, Articular / Q000166:cytology* / Q000187:drug effects*; D019902:Chondrocytes / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D015850:Interleukin-6 / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013111:Spider Venoms / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
chemical_list: D062565:Acid Sensing Ion Channels; D000143:Acids; D061067:Antibodies, Monoclonal, Humanized; D051017:Apoptosis Regulatory Proteins; D015850:Interleukin-6; D007770:L-Lactate Dehydrogenase; D010455:Peptides; D013111:Spider Venoms; D000093242:Interleukin-6 Inhibitors; C568268:Asic1 protein, rat; C413209:PcTX1 protein, Psalmopoeus cambridgei; C502936:tocilizumab
keywords: Acid-sensing ion channel 1a (ASIC1a); Apoptosis; Articular chondrocytes; IL-6; Rheumatoid arthritis