Matricellular Protein CCN1 Activates a Proinflammatory Genetic Program in Murine Macrophages

• Published in: The Journal of immunology (1950) Vol. 184; no. 6; pp. 3223 - 3232
• Main Authors: Bai, Tao, Chen, Chih-Chiun, Lau, Lester F
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.03.2010
• Subjects: Animals; Cell Adhesion - genetics; Cell Adhesion - immunology; Cell Line; Cell Line, Transformed; Cell Line, Tumor; Chemokines - biosynthesis; Chemokines - genetics; Cysteine-Rich Protein 61 - physiology; Cytokines - biosynthesis; Cytokines - genetics; Extracellular Matrix Proteins - physiology; Gene Expression Regulation - immunology; Inflammation Mediators - metabolism; Inflammation Mediators - physiology; Macrophage Activation - genetics; Macrophage Activation - immunology; Macrophage-1 Antigen - physiology; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Macrophages, Peritoneal - pathology; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; NF-kappa B - physiology; Oligonucleotide Array Sequence Analysis; Signal Transduction - genetics; Signal Transduction - immunology; Syndecan-4 - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0902792

CCN1 (CYR61) is a matricellular protein that is highly expressed at sites of inflammation and wound repair. In these contexts, CCN1 can modify the activities of specific cytokines, enabling TNF-alpha to be cytotoxic without blocking NF-kappaB activity and enhancing the apoptotic activity of Fas ligand and TRAIL. In this paper, we show that CCN1 supports the adhesion of macrophages through integrin alpha(M)beta(2) and syndecan-4, activates NFkappaB-mediated transcription, and induces a proinflammatory genetic program characteristic of classically activated M1 macrophages that participates in Th1 responses. The effects of CCN1 include upregulation of cytokines (TNF-alpha, IL-1alpha, IL-1beta, IL-6, and IL-12b), chemokines (MIP-1alpha; MCP-3; growth-related oncogenes 1 and 2; and inflammatory protein 10), and regulators of oxidative stress and complement (inducible NO synthase and C3) and downregulation of specific receptors (TLR4 and IL-10Rbeta) and anti-inflammatory factors (TGF-beta1). CCN1 regulates this genetic program through at least two distinct mechanisms: an immediate-early response resulting from direct activation of NF-kappaB by CCN1, leading to the synthesis of cytokines including TNF-alpha and inflammatory protein 10; and a delayed response resulting from CCN1-induced TNF-alpha, which acts as an autocrine/paracrine mediator to activate the expression of other cytokines including IL-1beta and IL-6. These results identify CCN1 as a novel component of the extracellular matrix that activates proinflammatory genes in macrophages, implicating its role in regulating macrophage function during inflammation.