We are interested in the regulation of B lym-phocyte maturation and activation to antibody production and in macrophage function in innate immunity. Engagement of the B cell antigen receptor, a membrane immunoglobulin associated with two signaling chains, leads to activation of intracellular tyrosine kinases, including Syk and the Src-family kinases Lyn, Fyn and Blk. We are studying the individual roles of these kinases, for example by studying B cells from mice deficient in Lyn. Surprisingly, these mice have hyperresponsive B cells due to an involvement of Lyn in inhibitory signaling events. Also, we are studying how downstream signaling events such as activation of Ras, PI 3-kinase, and PIP 2 breakdown are stimulated. We also want to know how these signaling events contribute to biological responses such as developmental maturation, survival, apoptosis, and proliferation.

Our other project involves the response of macrophages to bacterial lipopolysacchide (LPS), used as a first line of defense against bacterial infection. We have made considerable progress in identifying signaling events occurring in LPS-stimulated macrophages, including activation of the Erk and JNK MAP kinases, and in studying how they contribute to production of pro-inflammatory cytokines such as TNF-a.