MyD88-dependent activation of protein kinase D1 is essential for Group B streptococci-induced proinflammatory responses
Abstract
Group B streptococcus (GBS) causes life-threatening diseases, like pneumonia, septicemia and meningitis, in neonates. It has been reported that the pathogen-associated molecular patterns in GBS are recognized by pattern-recognition receptors, including Toll-like receptors (TLR), in the host innate immune cells. This recognition results in the cascades of inflammatory reactions. However, the molecular basis of GBS-induced proinflammatory responses are not yet completely elucidated. Protein kinase D1 (PKD1) has been identified as one of key signaling intermediaries that plays an indispensable role in proinflammatory responses mediated by TLRs. However, it is currently unknown whether PKD1 is activated, and contributes to proinflammatory responses induced by GBS. In the present study, the role of PKD1 in the proinflammatory responses to GBS is investigated. We found that both live and antibiotic-killed GBS activate PKD1 in human and murine cells. This PKD1 activation is dependent on the TLR signaling adaptor MyD88 and its downstream kinase IRAK1, but not TRAF6. Inhibition of PKD using a pharmacological inhibitor revealed that PKD1 is indispensable for GBS-mediated expression of various cytokines/chemokines in vitro and in vivo. Furthermore, systemic administration of PKD inhibitor protects D-galactosamine-sensitized mice from shock-mediated death caused by antibiotic-killed GBS. Our findings imply that PKD1 is one of the critical factors that play a regulatory role in…
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