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JNK1, but Not JNK2, Is Required in Two Mechanistically Distinct Models of Inflammatory Arthritis

  • The roles of the c-Jun N-terminal kinases (JNKs) in inflammatory arthritis have been investigated; however, the roles of each isotype (ie, JNK1 and JNK2) in rheumatoid arthritis and conclusions about whether inhibition of one or both is necessary for amelioration of disease are unclear. By using JNK1- or JNK2-deficient mice in the collagen-induced arthritis and the KRN T-cell receptor transgenic mouse on C57BL/6 nonobese diabetic (K/BxN) serum transfer arthritis models, we demonstrate that JNK1 deficiency results in protection from arthritis, as judged by clinical score and histological evaluation in both models of inflammatory arthritis. In contrast, abrogation of JNK2 exacerbates disease. In collagen-induced arthritis, the distinct roles of the JNK isotypes can, at least in part, be explained by altered regulation of CD86 expression in JNK1- or JNK2-deficient macrophages in response to microbial products, thereby affecting T-cell-mediated immunity. The protection from K/BxN serum-induced arthritis in Jnk1(-/-) mice can also be explained by inept macrophage function because adoptive transfer of wild-type macrophages to Jnk1(-/-) mice restored disease susceptibility. Thus, our results provide a possible explanation for the modest therapeutic effects of broad JNK inhibitors and suggest that future therapies should selectively target the JNK1 isoform.

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Metadaten
Document Type:Article
Language:English
Author:Katja Denninger, Susanne Rasmussen, Jeppe Madura Larsen, Catrine Ørskov, Steen Seier Poulsen, Poul Sørensen, Jan Pravsgaard Christensen, Harald Illges, Niels Ødum, Tord Labuda
Parent Title (English):Am J Pathol. (The American Journal of Pathology)
Volume:179
Issue:4
First Page:1884
Last Page:1893
ISSN:0002-9440
DOI:https://doi.org/10.1016/j.ajpath.2011.06.019
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=21839715
Publisher:Elsevier
Date of first publication:2011/08/11
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Institut für funktionale Gen-Analytik (IfGA)
Entry in this database:2015/04/02