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A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis.
J Immunol. 2004 Dec 01; 173(11):6928-37.JI

Abstract

TNF-alpha is a key factor in a variety of inflammatory diseases. This study examines the role of p38 MAPK in the regulation of TNF-alpha in primary human cells relevant to inflammation, e.g., macrophages and rheumatoid synovial cells. Using a dominant negative variant (D168A) of p38 MAPK and a kinase inhibitor, SB203580, we confirm in primary human macrophages that p38 MAPK regulates TNF-alpha production using a posttranscriptional mechanism requiring the 3' untranslated region of the gene. However, in LPS-activated primary human macrophages we also detect a second previously unidentified mechanism, the p38 MAPK modulation of TNF-alpha transcription. This is mediated through p38 MAPK regulation of NF-kappaB. Interestingly this mechanism was not observed in rheumatoid synovial cells. Importantly however, the dominant negative mutant of p38 MAPK, but not SB203580 was effective at inhibiting spontaneous TNF-alpha production in these ex vivo rheumatoid synovial cell cultures. These data indicate there are potential major differences in the role of p38 MAPK in inflammatory signaling that have a bearing on the use of this kinase as a target for therapy. These results indicate despite disappointing results with p38 MAPK inhibitors in the clinic, this kinase is a valid target in rheumatoid disease.

Authors+Show Affiliations

Kennedy Institute of Rheumatology Division, Imperial College School of Medicine Hammersmith, London, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15557189

Citation

Campbell, Jamie, et al. "A Novel Mechanism for TNF-alpha Regulation By P38 MAPK: Involvement of NF-kappa B With Implications for Therapy in Rheumatoid Arthritis." Journal of Immunology (Baltimore, Md. : 1950), vol. 173, no. 11, 2004, pp. 6928-37.
Campbell J, Ciesielski CJ, Hunt AE, et al. A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis. J Immunol. 2004;173(11):6928-37.
Campbell, J., Ciesielski, C. J., Hunt, A. E., Horwood, N. J., Beech, J. T., Hayes, L. A., Denys, A., Feldmann, M., Brennan, F. M., & Foxwell, B. M. (2004). A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis. Journal of Immunology (Baltimore, Md. : 1950), 173(11), 6928-37.
Campbell J, et al. A Novel Mechanism for TNF-alpha Regulation By P38 MAPK: Involvement of NF-kappa B With Implications for Therapy in Rheumatoid Arthritis. J Immunol. 2004 Dec 1;173(11):6928-37. PubMed PMID: 15557189.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis. AU - Campbell,Jamie, AU - Ciesielski,Cathleen J, AU - Hunt,Abigail E, AU - Horwood,Nicole J, AU - Beech,Jonathan T, AU - Hayes,Louise A, AU - Denys,Agnes, AU - Feldmann,Marc, AU - Brennan,Fionula M, AU - Foxwell,Brian M J, PY - 2004/11/24/pubmed PY - 2005/1/15/medline PY - 2004/11/24/entrez SP - 6928 EP - 37 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 173 IS - 11 N2 - TNF-alpha is a key factor in a variety of inflammatory diseases. This study examines the role of p38 MAPK in the regulation of TNF-alpha in primary human cells relevant to inflammation, e.g., macrophages and rheumatoid synovial cells. Using a dominant negative variant (D168A) of p38 MAPK and a kinase inhibitor, SB203580, we confirm in primary human macrophages that p38 MAPK regulates TNF-alpha production using a posttranscriptional mechanism requiring the 3' untranslated region of the gene. However, in LPS-activated primary human macrophages we also detect a second previously unidentified mechanism, the p38 MAPK modulation of TNF-alpha transcription. This is mediated through p38 MAPK regulation of NF-kappaB. Interestingly this mechanism was not observed in rheumatoid synovial cells. Importantly however, the dominant negative mutant of p38 MAPK, but not SB203580 was effective at inhibiting spontaneous TNF-alpha production in these ex vivo rheumatoid synovial cell cultures. These data indicate there are potential major differences in the role of p38 MAPK in inflammatory signaling that have a bearing on the use of this kinase as a target for therapy. These results indicate despite disappointing results with p38 MAPK inhibitors in the clinic, this kinase is a valid target in rheumatoid disease. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/15557189/A_novel_mechanism_for_TNF_alpha_regulation_by_p38_MAPK:_involvement_of_NF_kappa_B_with_implications_for_therapy_in_rheumatoid_arthritis_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=15557189 DB - PRIME DP - Unbound Medicine ER -