Chunguang Yan

Date of Award

January 2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Hongwei Gao

Abstract

CCAAT/enhancer-binding protein (C/EBP) &beta and C/EBP&delta are known to participate in the regulation of many genes associated with inflammation. However, little is known about the activation and function of C/EBP&beta and -&delta in inflammatory responses elicited by Fc&gamma receptor (Fc&gammaR) activation. Here I showed that C/EBP&beta and -&delta activation were induced in immunoglobulin G immune complex (IgG IC)-treated macrophages by using gel shift assays. The increased expression of C/EBP&beta and -&delta occurred at both mRNA and protein levels. Furthermore, induction of C/EBP&beta and -&delta was mediated, to a large extent, by activating Fc&gammaRs. Using small interfering RNA (siRNA)-mediated knockdown as well as macrophages deficient for C/EBP&beta and/or -&delta, I demonstrated that C/EBP&beta and -&delta played a critical role in the production of tumor necrosis factor-&alpha (TNF-&alpha), macrophage inflammatory protein-2 (MIP-2), and macrophage inflammatory protein-1&alpha (MIP-1&alpha) in IgG IC-stimulated macrophages. Moreover, both extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen activated protein kinase (MAPK) were involved in C/EBP induction and TNF-&alpha, MIP-2, and MIP-1&alpha production induced by IgG IC. I provided the evidence that complement component 5a (C5a) regulated IgG immune complex-induced inflammatory responses in macrophages by enhancing ERK1/2 and p38 MAPK activities as well as C/EBP&beta and -delta activities. To further explore the roles of C/EBP&beta and C/EBP&delta in Fc&gammaR-mediated inflammatory responses in vivo, I used IgG IC-induced acute lung injury model. I showed that both C/EBP&beta and C/EBP&delta activation were triggered in lungs challenged by IgG IC. I further demonstrated that C/EBP&beta but not C/EBP&delta deficient mice displayed significant attenuation of pulmonary vascular permeability and neutrophil accumulation when compared with wild type mice. Moreover, C/EBP&beta deficient mice expressed considerable less inflammatory mediators compared with wild type littermates. Together, these data indicate that both C/EBP&beta and C/EBP&delta act as inflammatory stimulators in vitro during IgG IC-mediated inflammation. However, it is C/EBP&beta but not C/EBP&delta depletion attenuates IgG IC-induced lung inflammatory reactions in vivo.

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