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* Department of Biology, University of North Carolina, Charlotte, NC 28223;
Section of Rheumatology, Department of Internal Medicine, and
Department of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520;
Center for Comparative Medicine, Schools of Medicine and Veterinary Medicine, University of California, Davis, CA 95616; and
¶ Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School and Howard Hughes Medical Institute, Worcester, MA 01605
Borrelia burgdorferi, the Lyme disease agent, causes
joint inflammation in an experimental murine model. Inflammation
occurs, in part, due to the ability of B. burgdorferi to
induce the production of proinflammatory cytokines and a strong
CD4+ T helper type 1 response. The mechanisms by which
spirochetes induce these responses are not completely known, although
transcription factors, such as NF-
B in phagocytic cells, initiate
the proinflammatory cytokine burst. We show here that the
mitogen-activated protein (MAP) kinase of 38 kDa (p38 MAP kinase) is
involved in the proinflammatory cytokine production elicited by
B. burgdorferi Ags in phagocytic cells and the
development of murine Lyme arthritis. B. burgdorferi Ags
activated p38 MAP kinase in vitro, and the use of a specific inhibitor
repressed the spirochete-induced production of TNF-
. The infection
of mice that are deficient for a specific upstream activator of the
kinase, MAP kinase kinase 3, resulted in diminished proinflammatory
cytokine production and the development of arthritis, without
compromising the ability of CD4+ T cells to respond to
borrelial Ags or the production of specific Abs. Overall, these data
indicated that the p38 MAP kinase pathway plays an important role in
B. burgdorferi-elicited inflammation and point to
potential new therapeutic approaches to the treatment of inflammation
induced by the spirochete.
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