Differential chemokine response of fibroblast subtypes to complement C1q.
OBJECTIVE
The pathogenesis of periodontitis includes an inappropriate activation of the classical complement cascade (C') with accumulation of inflammatory C' products in fluids and tissues. Our hypothesis is that in vivo the C' product, C1q, may act as a regulatory component of the innate immune response of distinct matrix fibroblasts to the inflammatory environment. This study analyzed the C1q induction of pro-inflammatory cytokine secretion in fibroblast subtypes derived from distinct periodontal tissues, and identified a mechanism of the cell response.


METHODS
Primary human gingival fibroblast, periodontal ligament fibroblast, and granulation tissue fibroblast cultures were treated for 24 h with C1q. Protein arrays assessed the secretory profile of constitutive and C1q-inducible pro-inflammatory cytokines, and enzyme-linked immunosorbent assays were used to quantify the kinetics of each inducible cytokine.


RESULTS
Granulation tissue fibroblast cultures were unresponsive to C1q challenge. In contrast, periodontal ligament fibroblasts responded with a release of monocyte chemoattractant protein (MCP)-1, interleukin-6, interleukin-8, and macrophage inflammatory protein (MIP)-1beta higher than the basal level by 8.2-, 7.0-, 3.8-, and 7.2-fold, respectively. Human gingival fibroblast cultures increased secretion of these chemokines by 5.2-, 4.5-, 3.0-, and 9.8-fold, respectively. Inhibitor studies revealed that C1q-inducible release of chemokines by the human gingival fibroblast and periodontal ligament cultures was contingent upon p38 mitogen-activated protein kinase activity.


CONCLUSIONS
The ability of C1q to stimulate secretion of pro-inflammatory chemokines depends upon which specific fibroblast subtype is involved. Targeting C1q-activated intracellular signaling pathways may be an effective means to inhibit the production of chemokines that promote inflammatory cell infiltration into gingival and periodontal ligament tissues.
Verardi
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Department of Periodontics, University of Washington, Seattle, WA 98195-7444, USA.
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Ammons
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Bordin
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D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D054407:Chemokine CCL4; D018925:Chemokines / Q000378:metabolism*; D019742:Chemokines, CC / Q000378:metabolism; D003167:Complement Activation / Q000276:immunology; D015922:Complement C1q / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology*; D005881:Gingiva / Q000166:cytology / Q000276:immunology*; D006097:Granulation Tissue / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D010513:Periodontal Ligament / Q000166:cytology / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology
C111835:CCL2 protein, human; C066507:CCL4 protein, human; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018925:Chemokines; D019742:Chemokines, CC; D016207:Cytokines; D007155:Immunologic Factors; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D015922:Complement C1q; D048051:p38 Mitogen-Activated Protein Kinases