Murine Lyme arthritis development mediated by p38 mitogen-activated protein kinase activity.
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-kappa 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-alpha. 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.
Anguita
Juan
J
Department of Biology, University of North Carolina, Charlotte, NC 28223, USA. janguita@email.unc.edu
Barthold
Stephen W
SW
Persinski
Rafal
R
Hedrick
Michael N
MN
Huy
Christy A
CA
Davis
Roger J
RJ
Flavell
Richard A
RA
Fikrig
Erol
E
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001170:Arthritis, Infectious / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D025065:Borrelia burgdorferi / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D002460:Cell Line; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D008193:Lyme Disease / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D048371:MAP Kinase Kinase 3; D020935:MAP Kinase Signaling System / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000172:deficiency / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D010586:Phagocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics; D017471:Receptors, Interferon / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases; D000096743:Interferon gamma Receptor
D000942:Antigens, Bacterial; D007371:Interferon-gamma; D048371:MAP Kinase Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011505:Protein-Tyrosine Kinases; D017471:Receptors, Interferon; D048051:p38 Mitogen-Activated Protein Kinases; D000096743:Interferon gamma Receptor; C482531:Map2k3 protein, mouse