Matricellular protein CCN1 activates a proinflammatory genetic program in murine macrophages.
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.
Bai
Tao
T
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
Chen
Chih-Chiun
CC
Lau
Lester F
LF
D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D055515:Cysteine-Rich Protein 61 / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D053671:Syndecan-4 / Q000502:physiology
C491850:CCN1 protein, mouse; D018925:Chemokines; D055515:Cysteine-Rich Protein 61; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D018836:Inflammation Mediators; D016177:Macrophage-1 Antigen; D016328:NF-kappa B; D053671:Syndecan-4