ArticleProceedings of the National Academy of Sciences of the United States of America2006
Mitogen-activated protein kinase kinase 3 is a pivotal pathway regulating p38 activation in inflammatory arthritis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 108 citations in OpenAlex.
- Lessons From the Success and Failure of Targeted Drugs for Rheumatoid Arthritis: Perspectives for Effective Basic and Translational Research.Immune network · 2022Review
- Discovery of the first chemical tools to regulate MKK3-mediated MYC activation in cancer.Bioorganic & medicinal chemistry · 2021Article
- Pseudomonas aeruginosa induces p38MAP kinase-dependent IL-6 and CXCL8 release from bronchial epithelial cells via a Syk kinase pathway.PloS one · 2021Article
- Pharmacological validation of targets regulating CD14 during macrophage differentiation.EBioMedicine · 2020Article
- High expression of MKK3 is associated with worse clinical outcomes in African American breast cancer patients.Journal of translational medicine · 2020Article
- Evaluation of the therapeutic potential of the selective p38 MAPK inhibitor Skepinone-L and the dual p38/JNK 3 inhibitor LN 950 in experimental K/BxN serum transfer arthritis.Inflammopharmacology · 2019Article
- Neutralization of Streptolysin S-Dependent and Independent Inflammatory Cytokine IL-1β Activity Reduces Pathology During Early Group AFrontiers in cellular and infection microbiology · 2018Article
- Dual Inhibition of Rip2 and IRAK1/4 Regulates IL-1β and IL-6 in Sarcoidosis Alveolar Macrophages and Peripheral Blood Mononuclear Cells.Journal of immunology (Baltimore, Md. : 1950) · 2016Article
- MKK3 mediates inflammatory response through modulation of mitochondrial function.Free radical biology & medicine · 2015Article
- Antileishmanial effect of 18β-glycyrrhetinic acid is mediated by Toll-like receptor-dependent canonical and noncanonical p38 activation.Antimicrobial agents and chemotherapy · 2015Article
- Roles of p38α mitogen-activated protein kinase in mouse models of inflammatory diseases and cancer.The FEBS journal · 2015Review
- Acid-sensing ion channel 3 decreases phosphorylation of extracellular signal-regulated kinases and induces synoviocyte cell death by increasing intracellular calcium.Arthritis research & therapy · 2014Article
- Relationship between serum IL10 level and p38MAPK enzyme activity on behavioral and cellular aspects of variation of hyperalgesia during different stages of arthritis in rats.Inflammopharmacology · 2014Article
- Inhibitory effects of intrathecal p38β antisense oligonucleotide on bone cancer pain in rats.International journal of clinical and experimental pathology · 2014Article
- Differential regulation of anti-inflammatory genes by p38 MAP kinase and MAP kinase kinase 6.Journal of inflammation (London, England) · 2014Article
- Differential roles of MAPK kinases MKK3 and MKK6 in osteoclastogenesis and bone loss.PloS one · 2014Article
- Acid-sensing ion channel 3 deficiency increases inflammation but decreases pain behavior in murine arthritis.Arthritis and rheumatism · 2013Article
- The role of the innate immune system in granulomatous disorders.Frontiers in immunology · 2013Article
- Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors.Nature reviews. Rheumatology · 2013Review
- Cellular targeting in autoimmunity.Current allergy and asthma reports · 2012Review
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
p38 mitogen-activated protein kinase (MAPK) regulates cytokines in arthritis and is, in turn, regulated by MAPK kinase (MKK) 3 and MKK6. To modulate p38 function but potentially minimize toxicity, we evaluated the utility of targeting MKK3 by using MKK3(-/-) mice. These studies showed that TNF-alpha increased phosphorylation of p38 in WT cultured synoviocytes but that p38 activation, IL-1beta, and IL-6 expression were markedly lower in MKK3(-/-) synoviocytes. In contrast, IL-1beta or LPS-stimulated p38 phosphorylation and IL-6 production by MKK3(-/-) synoviocytes were normal. Detailed signaling studies showed that NF-kappaB also contributes to IL-6 production and that TNF-alpha-induced NF-kappaB activation is MKK3-dependent. In contrast, LPS-mediated activation of NF-kappaB does not require MKK3. To determine whether this dichotomy occurs in vivo, two inflammation models were studied. In K/BxN passive arthritis, the severity of arthritis was dramatically lower in MKK3(-/-) mice. Phospho-p38, phospho-MAPK activator protein kinase 2, IL-1beta, CXC ligand 1, IL-6, and matrix metalloproteinase (MMP) 3 levels in the joints of MKK3(-/-) mice were significantly lower than in controls. Exogenous IL-1beta administered during the first 4 days of the passive model restored arthritis to the same severity as in WT mice. In the second model, IL-6 production after systemic LPS administration was similar in WT and MKK3(-/-) mice. Therefore, selective MKK3 deficiency can suppress inflammatory arthritis and cytokine production while Toll-like receptor 4-mediated host defense remains intact.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.