C1q arrests the cell cycle progression of fibroblasts in G(1) phase: role of the cAMP/PKA-I pathway.
C1q may participate in the loss of connective tissue occurring in chronic inflammatory lesions. The hypothesis of a detrimental role of C1q on cell proliferation was tested on primary cultures of human fibroblasts (HFs). C1q suppressed the DNA synthesis of HF in response to platelet-derived growth factor (PDGF) with an IC(50) of 20 microg/ml, and blocked 78% of the cycling cells in G(1) phase. The C1q block did not involve production of inhibitory prostaglandin by the cells. Given that C1q elicits signals of the adenylyl cyclase pathway in HF, we examined cAMP-dependent mechanisms to understand how C1q inhibited the PDGF response. Whereas the C1q block was enhanced by agonist dibutyryl-adenosine 3', 5'-cyclic mono-phosphate (db-cAMP), antagonist adenosine 3', 5'-cyclic monophosphorotioate triethylammonium salt (Rp-cAMP) minimized it. C1q increased the level of cAMP-dependent protein kinase I (PKA-I) 4.5-fold, without altering the activation of the extracellular-regulated protein kinase (ERK) pathway. These results demonstrate that the interactions of C1q with HF cause growth arrest at the G(1) phase through mechanisms associated with a PKA-I dependent pathway.
Department of Periodontics, University of Washington, PO Box 357444, Seattle, WA 98195, USA. bordin@u.washington.edu
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D000328:Adult; D015153:Blotting, Western; D003994:Bucladesine / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects; D005881:Gingiva / Q000166:cytology; D006801:Humans; D020128:Inhibitory Concentration 50; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013873:Thionucleotides / Q000494:pharmacology
D004791:Enzyme Inhibitors; D010982:Platelet-Derived Growth Factor; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D003994:Bucladesine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone