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J. Biol. Chem., Vol. 282, Issue 10, 7360-7367, March 9, 2007

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Generation of Inhibitory NFB Complexes and Phosphorylated cAMP Response Element-binding Protein Correlates with the Anti-inflammatory Activity of Complement Protein C1q in Human Monocytes^*

From the Department of Molecular Biology and Biochemistry, Center for Immunology, University of California, Irvine, California 92697

The interaction of C1q with specific cells of the immune system induces activities, such as enhancement of phagocytosis in monocytes and stimulation of superoxide production in neutrophils. In contrast to some other monocyte activators, C1q itself does not induce pro-inflammatory cytokine production, but rather inhibits the lipopolysaccharide (LPS)-stimulated induction of certain pro-inflammatory cytokines and induces expression of interleukin-10. To investigate the molecular mechanism by which C1q exerts this effect on gene expression, the influence of C1q on the activation of transcription factors of the NFB family and cAMP response element-binding protein (CREB) was assessed. C1q treatment increased B binding activity in freshly isolated human monocytes in a time-dependent fashion as assessed by electrophoretic mobility shift assays. In antibody supershift experiments, anti-p50 antibody supershifted the C1q-induced NFB complex, whereas anti-p65 antibody had little effect, suggesting that C1q induced the translocation of NFB p50p50 homodimers. This is in contrast to the dominant induction of p65 containing complexes in parallel monocyte cultures stimulated with LPS. C1q treatment also induced cAMP response element (CRE)-binding activity as demonstrated by electrophoretic mobility shift assay, increased phosphorylation of CREB, and induction of CRE driven gene expression. In contrast, CREB activation was not detected in LPS-treated monocytes. These results suggest that C1q may modulate the cytokine profile expressed in response to inflammatory stimuli (e.g. LPS), by triggering inhibitory and/or competing signals. Because C1q and other defense collagens have been shown to enhance clearance of apoptotic cells, this regulatory pathway may be beneficial in avoiding autoimmunity and/or resolving inflammation.

Received for publication, June 15, 2006 , and in revised form, December 8, 2006.

^* This work was supported by National Institutes of Health Grant AI41090 (to A. J. T.) and support for obtaining human blood products used in this study was provided in part by United States Public Health Service Research Grant M01 RR00827 from the National Center for Research Resources. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Current address: Dept. of Medicine, University of Pittsburgh, Pittsburgh, PA.

² Current address: Dept. of Microbiology and Immunology, Indiana University School of Medicine-South Bend, South Bend, IN 46617.

³ Current address: Dpto. de Biodiversidad y Biologia Evolutiva, Museo Nacional de Ciencias Naturales, CSIC, 28006 Madrid, Spain.

⁴ To whom correspondence should be addressed: 3205 McGaugh Hall, Dept. of Molecular Biology & Biochemistry, University of California, Irvine, CA 92697. Tel.: 949-824-3268; Fax: 949-824-8551; E-mail: atenner{at}uci.edu.

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