MIP-1α Induces Differential MAP Kinase Activation and IκB Gene Expression in Human B Lymphocytes

Abstract

The chemokine macrophage inflammatory protein-1α (MIP-1α) stimulates migration of B cells and affects B cell immunoglobulin production. However, the molecular mechanisms by which MIP-1α modulates these biologic effects have not been completely defined. Previously, we demonstrated that treatment of B cells with MIP-1α induced the transcription factor, nuclear factor (NF)-κB, to bind to DNA, concomitant with the degradation of IκBα, a cytoplasmic inhibitor of NF-κB activation. Here, we report that MIP-1α treatment of tonsil B cells induced IκB gene expression that was dependent on MIP-1α-mediated activation of a pathway(s) involving NF-κB and phosphatidylinositol-3 kinase (PI3K). The NF-κB pathway is understood to be controlled in an autoregulatory fashion, so expression of IκB is thought to provide a means by which B cells modulate this pathway after stimulation with MIP-1α. Although the idea of NF-κB autoregulation is not novel, this is the first report to suggest the regulation of B cell gene expression by MIP-1α. In addition, we observed the activation of Jun N-terminal kinase (JNK) and p38 mitogenic-activated protein kinase (MAPK), but not extracellular signal-related kinase (ERK) in response to MIP-1α. Although p38 and NF-κB activity were both necessary for B cell migration, IκB gene expression was not affected by p38 inhibition, suggesting that p38 is involved in a separate MIP-1α-mediated signal transduction pathway.