ArticleArthritis and rheumatism2012
Antiinflammatory functions of p38 in mouse models of rheumatoid arthritis: advantages of targeting upstream kinases MKK-3 or MKK-6.
Article in Arthritis and rheumatism, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 80 citations in OpenAlex.
- Functionalized hydrocaffeic acid-chitosan/EGTA hydrogel rescues mitochondrial dysfunction for immunomodulation and joint repair in rheumatoid arthritis.Materials today. Bio · 2025Article
- Enhancing the effectiveness of immunotherapy in rheumatoid arthritis by delaying immunosenescence triggered by fibroblast-like synoviocytes.Journal of orthopaedic surgery and research · 2025Review
- Sex Dependent Disparities in the Central Innate Immune Response after Moderate Spinal Cord Contusion in Rat.Cells · 2024Article
- Suppression of CGRP and TRPV1 Expression in Dorsal Root Ganglia of Knee Osteoarthritis Rats by Huojing Decoction via TrkA/MKK3/6/p38 Pathway.Journal of inflammation research · 2024Article
- Advances of the small molecule drugs regulating fibroblast-like synovial proliferation for rheumatoid arthritis.Frontiers in pharmacology · 2023Review
- Stress signaler p38 mitogen-activated kinase activation: a cause for concern?Clinical science (London, England : 1979) · 2022Article
- Article
- Terpenoids fromInternational journal of molecular sciences · 2021Article
- Hydrogen Sulfide: a Novel Immunoinflammatory Regulator in Rheumatoid Arthritis.Advances in experimental medicine and biology · 2021Review
- Biochanin A impedes STAT3 activation by upregulating p38δ MAPK phosphorylation in IL-6-stimulated macrophages.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2020Article
- Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes.Nature reviews. Rheumatology · 2020Review
- The sex-specific role of p38 MAP kinase in CNS autoimmunity is regulated by estrogen receptor alpha.Journal of neuroimmunology · 2020Article
- Fibroblast Growth Factor Receptor 4 Deficiency Mediates Airway Inflammation in the Adult Healthy Lung?Frontiers in 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
- MKK3 sustains cell proliferation and survival through p38DELTA MAPK activation in colorectal cancer.Cell death & disease · 2019Article
- Insights of Crosstalk between p53 Protein and the MKK3/MKK6/p38 MAPK Signaling Pathway in Cancer.Cancers · 2018Review
- Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation.Nature communications · 2018Article
- Ontology and Function of Fibroblast-Like and Macrophage-Like Synoviocytes: How Do They Talk to Each Other and Can They Be Targeted for Rheumatoid Arthritis Therapy?Frontiers in immunology · 2018Review
- Inflammation-regulated mRNA stability and the progression of vascular inflammatory diseases.Clinical science (London, England : 1979) · 2017Review
- Anti-inflammatory roles of p38α MAPK in macrophages are context dependent and require IL-10.Journal of leukocyte biology · 2017Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
objectiveInhibitors of p38 demonstrate limited benefit in rheumatoid arthritis (RA), perhaps due to the antiinflammatory functions of p38α. This study was performed to determine if selective deletion of p38α in macrophages affects the severity of arthritis and whether blocking upstream kinases in the p38 pathway, such as MKK-3 or MKK-6, avoids some of the limitations of p38 blockade.
methodsWild-type (WT) mice and mice with selective deletion of p38α in macrophages (p38α(ΔLysM) ) were injected with K/BxN sera. Antigen-induced arthritis was also induced in p38α(ΔLysM) mice. Mouse joint extracts were evaluated by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction (qPCR), and Western blot analysis. Bone marrow-derived macrophages (BMMs) were stimulated with lipopolysaccharide (LPS) and were evaluated by qPCR and Western blotting. Bone marrow chimeras were generated using MKK-3(-/-) and MKK-6(-/-) mice, and K/BxN serum was administered to induce arthritis.
resultsCompared to WT mice, p38α(ΔLysM) mice had increased disease severity and delayed resolution of arthritis, which correlated with higher synovial inflammatory mediator expression and ERK phosphorylation. In contrast to WT BMMs cultured in the presence of a p38α/β inhibitor, LPS-stimulated MKK-6- and MKK-3-deficient BMMs had suppressed LPS-mediated interleukin-6 (IL-6) expression but had normal IL-10 production, dual-specificity phosphatase 1 expression, and MAPK phosphorylation. WT chimeric mice with MKK-6- and MKK-3-deficient bone marrow had markedly decreased passive K/BxN arthritis severity.
conclusionInhibiting p38α in a disease that is dominated by macrophage cytokines, such as RA, could paradoxically suppress antiinflammatory functions and interfere with clinical efficacy. Targeting an upstream kinase that regulates p38 could be more effective by suppressing proinflammatory cytokines while preventing decreased IL-10 expression and increased MAPK activation.
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