C5a-regulated CCAAT/enhancer-binding proteins ß and δ are essential in Fcγ receptor-mediated inflammatory cytokine and chemokine production in macrophages.

CCAAT/enhancer-binding protein ß (C/EBPß) and C/EBPδ are known to participate in the regulation of many genes associated with inflammation. However, little is known about the activation and function of C/EBPß and -δ in inflammatory responses elicited by Fcγ receptor (FcγR) activation. Here we show that C/EBPß and -δ activation are induced in IgG immune complex (IC)-treated macrophages. The increased expression of C/EBPß and -δ occurred at both mRNA and protein levels. Furthermore, induction of C/EBPß and -δ was mediated, to a large extent, by activating FcγRs. Using siRNA-mediated knockdown as well as macrophages deficient for C/EBPß and/or -δ, we demonstrate that C/EBPß and -δ play a critical role in the production of TNF-α, MIP-2, and MIP-1α in IgG IC-stimulated macrophages. Moreover, both ERK1/2 and p38 MAPK are involved in C/EBP induction and TNF-α, MIP-2, and MIP-1α production induced by IgG IC. We provide the evidence that C5a regulates IgG IC-induced inflammatory responses by enhancing ERK1/2 and p38 MAPK activities as well as C/EBPß and -δ activities. Collectively, these data suggest that C/EBPß and -δ are key regulators for FcγR-mediated induction of cytokines and chemokines in macrophages. Furthermore, C/EBPs may play an important regulatory role in IC-associated inflammatory responses.