Alternative p38 MAPKs are essential for collagen-induced arthritis.
OBJECTIVE
The role of most p38 MAPK isoforms in inflammatory arthritis is not known. This study was undertaken to evaluate p38γ and p38δ deficiency in the collagen-induced arthritis (CIA) model.


METHODS
Wild-type, p38γ(-/-) , p38δ(-/-) , and p38γ/δ(-/-) mice were immunized with chicken type II collagen, and disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum cytokine levels and in vitro T cell cytokine responses were quantified by flow cytometry and multiplex analysis, and serum anticollagen antibody levels by enzyme-linked immunosorbent assay. Cytokine and p38 MAPK isoform expression in joints were determined by quantitative polymerase chain reaction.


RESULTS
Compound p38γ and p38δ deficiency markedly reduced arthritis severity compared with that in wild-type mice, whereas lack of either p38γ or p38δ had an intermediate effect. Joint damage was minimal in arthritic p38γ/δ(-/-) mice compared with wild-type mice. The p38γ/δ(-/-) mice had lower levels of pathogenic anticollagen antibodies and interleukin-1β (IL-1β) and tumor necrosis factor α than controls. In vitro T cell assays showed reduced proliferation, interferon-γ (IFNγ) production, and IL-17 production by lymph node cells from p38γ/δ(-/-) mice. IL-17 and IFNγ messenger RNA expression in joints was significantly inhibited in p38γ/δ(-/-) mice. Wild-type chimeric mice with p38γ/δ(-/-) bone marrow did not show decreased CIA.


CONCLUSIONS
Reduced disease severity in p38γ/δ(-/-) mice was associated with lower cytokine production and anticollagen antibody responses than in controls, indicating that p38γ and p38δ are crucial regulators of inflammatory joint destruction in CIA. Our findings indicate that p38γ and p38δ are potential therapeutic targets in complex diseases, such as rheumatoid arthritis, that involve innate and adaptive immune responses.
Instituto de Investigación Sanitaria and Hospital Universitario 12 de Octubre, Madrid, Spain.
Gabriel
G
Criado
Ana
A
Risco
Dayanira
D
Alsina-Beauchamp
María J
MJ
Pérez-Lorenzo
Alejandra
A
Escós
Ana
A
Cuenda
D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048291:Mitogen-Activated Protein Kinase 12 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048292:Mitogen-Activated Protein Kinase 13 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020381:Interleukin-17; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D048291:Mitogen-Activated Protein Kinase 12; D048292:Mitogen-Activated Protein Kinase 13