The role of p38 mitogen‐activated protein kinase in IL‐6 and IL‐8 production from the TNF‐α‐ or IL‐1β‐stimulated rheumatoid synovial fibroblasts

Suzuki, Masaki; Tetsuka, T.; Yoshida, Shigeaki; Watanabe, Nobuyuki; Kobayashi, Mariko; Matsui, Nobuo; Okamoto, Takashi

doi:10.1016/s0014-5793(99)01717-2

Cited by 177 publications

(121 citation statements)

References 30 publications

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“…Upon cellular stimulation, IκB-α protein is phosphorylated and targeted for ubiquitination and subsequent degradation by the 26S proteosome (Chang and Karin 2001). NF-κB subsequently is released and translocated to the nucleus to activate the expression of various target genes (Suzuki et al 2000;Wang et al 2003). Pro-inflammatory cytokines such as TNF-α and IL-1β can also activate NF-κB through signal transduction involving the TNF receptor associated factor (TRAF) family of adaptor proteins (Dempsey et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Evidence that Cisplatin-induced Auditory Damage is Attenuated by Downregulation of Pro-inflammatory Cytokines Via Nrf2/HO-1

Kim

et al. 2008

JARO

108

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Recently, we demonstrated that pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 played a critical role in cisplatin-induced cochlear injury and that flunarizine, known as a T-type Ca 2+ channel antagonist, induced a cytoprotective effect against cisplatin cytotoxicity in HEI-OC1 cells by the activation of NF-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) cascade through PI3K-Akt signaling but calciumindependent pathway. We report here that flunarizine markedly attenuates cisplatin-induced pro-inflammatory cytokine secretion and their messenger RNA transcription as well as cisplatin cytotoxicity through the activation of Nrf2/HO-1 and downregulation of NF-κB. In HEI-OC1 cells, overexpression of Nrf2/HO-1 by gene transfer or pharmacological approaches attenuated cisplatin-induced cytotoxicity and proinflammatory cytokine production. On the contrary, inhibition of Nrf2/HO-1 signaling by pharmacological inhibitors or specific small interfering RNAs significantly abolished the beneficial effects of flunarizine. Flunarizine also attenuated cisplatin-mediated MAPK activation and pharmacological inhibition of MAPKs, especially MEK1/ERK, blocked cisplatin-induced NF-κB activation in HEI-OC1 cells. Furthermore, WT-Nrf2 overexpression effectively blocked MAPK activation after cisplatin exposure. Finally, orally administrated Sibelium™, the trade name of flunarizine, suppressed the increase of pro-inflammatory cytokines by cisplatin in both serum and cochleas of mice, whereas it increased HO-1 expression in cochleas. These results indicate that flunarizine induces a protective effect against cisplatin ototoxicity through the downregulation of NF-κB by Nrf2/HO-1 activation and the resulting inhibition of pro-inflammatory cytokine production in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

Evidence that Cisplatin-induced Auditory Damage is Attenuated by Downregulation of Pro-inflammatory Cytokines Via Nrf2/HO-1

Kim

et al. 2008

JARO

108

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“…As a matter of fact, p38 MAPK plays a major role in facilitating the cytokine activation induced by TNF. Induction of proinflammatory mediators such as IL-1 and IL-6 by TNF is mediated by activation of p38 MAPK (31). Of note, these cytokines are inducibly expressed in these initial stages of arthritis and appear to be selectively linked to the areas of onset of inflammation, such as the cellular infiltration of the tendon sheaths.…”

Section: Discussionmentioning

confidence: 99%

Tenosynovitis and osteoclast formation as the initial preclinical changes in a murine model of inflammatory arthritis

Hayer¹,

Redlich²,

Korb³

et al. 2007

Arthritis & Rheumatism

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Objective. To determine the nature of the initial changes of joint inflammation occurring before, at the time of, and shortly after onset of clinically apparent arthritis.Methods. Human tumor necrosis factor (TNF)-transgenic mice were assessed for clinical, histologic, immunophenotypic, serologic, and molecular changes at the preclinical phase of arthritis, at the onset of disease, and at the stage of early clinical disease. In addition, the effects of a genetic osteoclast deficiency and pharmacologic inhibition of TNF were studied in these initial phases of disease.Results. Initial articular changes were observed even before the start of clinical symptoms. Infiltration of the tendon sheaths by granulocytes and macrophages as well as formation of osteoclasts next to the inflamed tendon sheaths were the first pathologic events. Tenosynovitis rapidly led to remodeling of the sheaths into pannus-like tissue, which formed osteoclasts that invaded the adjacent mineralized cartilage. Early lesions were associated with up-regulation of interleukin-1 (IL-1) and IL-6 as well as activation of p38 MAPK and ERK. In contrast, absence of osteoclasts led to uncoupling of tenosynovitis from invasion into cartilage and bone. TNF blockade also attenuated the pathologic changes associated with tenosynovitis.Conclusion. Structural damage begins even before the onset of clinical symptoms of arthritis and involves the tendon sheaths as well as adjacent cartilage and bone. These results suggest that tenosynovitis is an initiating feature of arthritis and that joint destruction starts right from the onset of disease. Our findings thus underscore the importance of immediate initiation of an effective therapy in patients with rheumatoid arthritis.

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“…2 The p38 MAP kinase is of particular interest in inflammatory diseases such as rheumatoid arthritis (RA) because it regulates the production of pathogenic cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-␣. 3,4 p38 is expressed and activated in RA synovium 5 and blockade using selective inhibitors decreases inflammation and bone destruction animal models of arthritis. 6 However, little is known about the upstream kinases that can activate this pathway in joint tissues.…”

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confidence: 99%

Expression and Activation of Mitogen-Activated Protein Kinase Kinases-3 and -6 in Rheumatoid Arthritis

Chabaud-Riou¹,

Firestein²

2004

The American Journal of Pathology

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The p38 mitogen-activated protein (MAP) kinase signal transduction pathway regulates the production of interleukin-1 and tumor necrosis factor-␣. p38 kinase inhibitors are effective in animal models of arthritis and are currently being developed in rheumatoid arthritis (RA). However, little is known about the upstream kinases that control the activation of p38 in RA synovium. In vitro studies previously identified the MAP kinase kinases (MAPKKs) MKK3 and MKK6 as the primary regulators of p38 phosphorylation and activation. To investigate a potential role for MKK3 and MKK6 in RA, we evaluated their expression and regulation in RA synovium and cultured fibroblastlike synoviocytes (FLS). Immunohistochemistry demonstrated that MKK3 and MKK6 are expressed in RA and osteoarthritis (OA) synovium. Digital image analysis showed no significant differences between OA and RA with regard to expression or distribution. However, phosphorylated MKK3/6 expression was significantly higher in RA synovium and was localized to the sublining mononuclear cells and the intimal lining. Actin-normalized Western blot analysis of synovial tissue lysates confirmed the increased expression of phosphorylated MKK3/6 in RA. Western blot analysis demonstrated constitutive expression of MKK3 and MKK6 in RA and OA FLS. Phospho-MKK3 levels were low in medium-treated FLS, but were rapidly increased by interleukin-1 and tumor necrosis factor-␣, although phospho-MKK6 levels only modestly increased. p38 co-immunoprecipitated with MKK3 and MKK6 from cytokine-stimulated FLS and the complex phosphorylated activating transcription factor-2 in an in vitro kinase assay. These data are the first documentation of MKK3 and MKK6 activation in human inflammatory disease. By forming a complex with p38 in synovial tissue and FLS, these kinases can potentially be targeted to regulate the production of proinflammatory cytokine production in inflamed synovium. (Am J Pathol 2004, 164:177-184) Mitogen-activated protein (MAP) kinases are a family of serine/threonine kinases that mediate signal transduction and orchestrate an appropriate cellular response to environmental stress. In mammalian cells, three principle MAP kinase pathways have been identified, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. 1 Multiple MAP kinase pathways can be simultaneously activated and the relative balance is determined by the parallel upstream kinase cascades known as MAP kinase kinases (MAPKKs) and MAP kinase kinase kinases (MAP3Ks). 2 The p38 MAP kinase is of particular interest in inflammatory diseases such as rheumatoid arthritis (RA) because it regulates the production of pathogenic cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-␣. 3,4 p38 is expressed and activated in RA synovium 5 and blockade using selective inhibitors decreases inflammation and bone destruction animal models of arthritis. 6 However, little is known about the upstream kinases that can activate this pathway in joint tissues. Of the MAPKKs, MKK3 a...

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The role of p38 mitogen‐activated protein kinase in IL‐6 and IL‐8 production from the TNF‐α‐ or IL‐1β‐stimulated rheumatoid synovial fibroblasts

Cited by 177 publications

References 30 publications

Evidence that Cisplatin-induced Auditory Damage is Attenuated by Downregulation of Pro-inflammatory Cytokines Via Nrf2/HO-1

Evidence that Cisplatin-induced Auditory Damage is Attenuated by Downregulation of Pro-inflammatory Cytokines Via Nrf2/HO-1

Tenosynovitis and osteoclast formation as the initial preclinical changes in a murine model of inflammatory arthritis

Expression and Activation of Mitogen-Activated Protein Kinase Kinases-3 and -6 in Rheumatoid Arthritis

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