The IκB Kinase Complex and NF-κB Actas Master Regulators of Lipopolysaccharide-Induced Gene Expressionand Control Subordinate Activation ofAP-1

Abstract

Toll-like receptors (TLRs) recognize conserved products of microbial pathogens to initiate the innate immune response. TLR4 signaling is triggered upon binding of lipopolysaccharides (LPS) from gram-negative bacteria. Using comparative gene expression profiling, we demonstrate a master regulatory role of IκB kinase (IKK)/NF-κB signaling for immediate-early gene induction after LPS engagement in precursor B cells. IKK/NF-κB signaling controls a large panel of gene products associated with signaling and transcriptional activation and repression. Intriguingly, the induction of AP-1 activity by LPS in precursor B cells and primary dendritic cells fully depends on the IKK/NF-κB pathway, which promotes expression of several AP-1 family members, including JunB, JunD, and B-ATF. In pre-B cells, AP-1 augments induction of a subset of primary NF-κB targets, as shown for chemokine receptor 7 (CCR7) and immunoglobulin κ light chain. Thus, our data illustrate that NF-κB orchestrates immediate-early effects of LPS signaling and controls secondary AP-1 activation to mount an appropriate biological response.

We thank Erika Scharschmidt and Sabine Jungmann for expert technical assistance and Charles Vinson for providing A-Fos.

This work was supported in part by grants from Deutsche Forschungsgemeinschaft and National Genome Research Network NGFN to C.S.