ArticleThe American journal of pathology2004
Expression and activation of mitogen-activated protein kinase kinases-3 and -6 in rheumatoid arthritis.
Article in The American journal of pathology, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
21 citing papers in PubMed, 69 citations in OpenAlex.
- GPR143 mediates virus-induced cytoplasmic vacuolation through the MKK6-p38 pathway in teleosts.Zoological research · 2026Article
- Integrated analysis reveals NLRC4 as a potential biomarker in sepsis pathogenesis.Genes and immunity · 2024Article
- Evolutionary history of MEK1 illuminates the nature of deleterious mutations.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Stress signaler p38 mitogen-activated kinase activation: a cause for concern?Clinical science (London, England : 1979) · 2022Article
- Non-'classical' MEKs: A review of MEK3-7 inhibitors.Bioorganic & medicinal chemistry letters · 2020Review
- Roles of p38α mitogen-activated protein kinase in mouse models of inflammatory diseases and cancer.The FEBS journal · 2015Review
- Article
- GADD45α induction by nickel negatively regulates JNKs/p38 activation via promoting PP2Cα expression.PloS one · 2013Article
- Decreased collagen-induced arthritis severity and adaptive immunity in MKK-6-deficient mice.Arthritis and rheumatism · 2012Article
- The p38 MAPK Pathway in Rheumatoid Arthritis: A Sideways Look.The open rheumatology journal · 2012Article
- Hck is a key regulator of gene expression in alternatively activated human monocytes.The Journal of biological chemistry · 2011Article
- Pharmacogenetics: implications for therapy in rheumatic diseases.Nature reviews. Rheumatology · 2011Review
- Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome.Pharmaceuticals (Basel, Switzerland) · 2010Review
- Pomegranate extract inhibits the interleukin-1β-induced activation of MKK-3, p38α-MAPK and transcription factor RUNX-2 in human osteoarthritis chondrocytes.Arthritis research & therapy · 2010Article
- "Go upstream, young man": lessons learned from the p38 saga.Annals of the rheumatic diseases · 2010Review
- MKK3, an upstream activator of p38, contributes to formalin phase 2 and late allodynia in mice.Neuroscience · 2009Article
- Role of MAPK kinase 6 in arthritis: distinct mechanism of action in inflammation and cytokine expression.Journal of immunology (Baltimore, Md. : 1950) · 2009Article
- Update on Targets of Biologic Therapies for Rheumatoid Arthritis.Current rheumatology reviews · 2008Article
- The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis.Annals of the rheumatic diseases · 2008Review
- Mitogen-activated protein kinase kinase 3 is a pivotal pathway regulating p38 activation in inflammatory arthritis.Proceedings of the National Academy of Sciences of the United States of America · 2006Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The p38 mitogen-activated protein (MAP) kinase signal transduction pathway regulates the production of interleukin-1 and tumor necrosis factor-alpha. 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 fibroblast-like 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-alpha, 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.
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