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      Matricellular protein CCN1 activates a proinflammatory genetic program in murine macrophages.

      The Journal of Immunology Author Choice
      Animals, Cell Adhesion, genetics, immunology, Cell Line, Cell Line, Transformed, Cell Line, Tumor, Chemokines, biosynthesis, Cysteine-Rich Protein 61, physiology, Cytokines, Extracellular Matrix Proteins, Gene Expression Regulation, Inflammation Mediators, metabolism, Macrophage Activation, Macrophage-1 Antigen, Macrophages, Peritoneal, pathology, Male, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, NF-kappa B, Oligonucleotide Array Sequence Analysis, Signal Transduction, Syndecan-4

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          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.

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