Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.0308219 on December 12, 2008

Published online before print December 12, 2008
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(Journal of Leukocyte Biology. 2009;85:539-543.)
© 2009 by Society for Leukocyte Biology

Regulation of TLR4-mediated signaling by IBP/Def6, a novel activator of Rho GTPases

Qinzhong Chen, Sanjay Gupta and Alessandra B. Pernis1

Department of Medicine, Columbia University, New York, New York, USA

1 Correspondence: Department of Medicine, Columbia University, 630 West 168th Street, New York, NY 10032, USA. E-mail: abp1{at}columbia.edu

TLRs play a fundamental role in innate immune responses. Although Rho GTPases have been implicated in TLR-mediated signaling pathways, the molecules that control their activation in response to TLR engagement are largely unknown. IFN regulatory factor-4-binding protein (IBP; which is encoded by the gene Def6) is a unique type of activator for Rac that plays a crucial role in TCR-mediated signaling and adaptive immune responses. Here, we demonstrate that IBP/Def6 also controls innate immune responses by modulating TLR-induced signaling events. Mice deficient in IBP/Def6 are protected from LPS-induced septic shock. This protection is associated with a decrease in the production of proinflammatory cytokines and is accompanied by diminished activation of MAPKs and NF-{kappa}B. Our results thus identify IBP/Def6 as a novel component of the TLR4-induced signaling cascade that controls the production of proinflammatory cytokines.

Key Words: proinflammatory cytokines • MAPK • NF-{kappa}B • GEF