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The role of the p38 mitogen-activated protein kinase in the immune response

University of British Columbia

The p38 mitogen-activated protein kinases (p38 MAPKs) were originally shown to be activated in response to environmental stress and pro-inflammatory cytokines. This thesis investigates the hypothesis that p38 MAPK would be activated by other stimuli other than stress, such as those involved in the regulation of the immune response. In T cells, crosslinking of the CD3 chains of the T cell antigen receptor (TCR) complex or of Fas resulted in activation of p38 MAP kinase and MAPKAP kinase-2. Crosslinking of CD28 synergized with low doses of anti- CD3 to activate p38 MAP kinase or MAPKAP kinase-2. The in vivo activation of MAPKAP kinase-2 in response to crosslinking of CD3 and CD28 or Fas was shown to be dependent on p38 MAP kinase activity using SB 203580, a specific inhibitor of p38 MAPK α and β. Crosslinking of the B cell antigen receptor (BCR) or CD40 on B cells also resulted in activation of p38 MAP kinase and MAPKAP kinase-2. Next, a possible role for p38 MAPK in apoptosis triggered by ligation of antigen receptors on lymphocytes was investigated. When used at concentrations which suppressed the in vivo activation of MAPKAP kinase-2, SB 203580 did not inhibit activation-induced cell death in T cells or BCR-induced apoptosis in the immature B lymphoma WEHI 231 cells. We conclude that the activation of p38 MAP kinase and MAPKAP kinase-2 by crosslinking of the TCR, BCR, Fas or CD40 was not correlated with their role in regulating lymphocyte survival. Experiments with SB 203580 also demonstrated a role for p38 MAPK in the synthesis of cytokines. The antigen-initiated production both of IL-12 by splenic antigen-presenting cells (APCs) and of IFNγ by CD4+ T cells were regulated by p38 MAPK. In contrast, SB 203580 enhanced the production of IL-12 elicited from macrophages by stimulation with lipopolysaccharide (LPS). The enhancement of IL-12 production correlated with the inhibition of IL-10 by SB 203580, a known negative regulator of IL-12 production in LPS-stimulated macrophages. These results demonstrate that p38 MAP kinase is not only a "stress-activated kinase" but also plays a role in the regulation of both innate and antigen-specific immune responses. [Scientific formulae used in this abstract could not be reproduced.]

Thesis/Dissertation

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2009-07-02

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http://hdl.handle.net/2429/9994

Experimental Medicine

University of British Columbia

UBCV

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