Retinoic acid potentiates interleukin-1- and fibroblast growth factor-induced human synovial fibroblast proliferation.
All trans-retinoic acid (ATRA) and related compounds, at concentrations ranging from 10(-8) to 10(-6) M, augmented the proliferation of human synovial fibroblasts (HSN) stimulated by human interleukin-1 alpha or -beta (IL-1 alpha, IL-beta) and both the acidic and basic forms of fibroblast growth factor (FGFa, FGFb). In contrast, ATRA had no effect on human tumor necrosis factor alpha (TNF alpha)-induced HSN proliferation. The potentiation of HSN proliferation was completely dependent on the presence of IL-1 or FGF since HSN were unresponsive to ATRA alone. The mechanism by which ATRA enhances IL-1-induced HSN proliferation does not appear mediated by changes in the affinity or number of IL-1 receptors expressed by HSN; however, treatment with dexamethasone (DEX, 10(-6)M) resulted in a twofold increase in IL-1 receptor number. ATRA inhibited both IL-1 beta- and TNF alpha-induced secretion of prostaglandin-E2 (PGE2), a potent feedback inhibitor of cytokine-stimulated HSN proliferation. However, the synergistic effect of ATRA on IL-1- or FGF-induced proliferation did not appear related to the secretion of cyclooxygenase products since ATRA had no effect on TNF alpha-induced HSN proliferation and indomethacin was included in all HSN proliferation experiments. The results of this study suggest that ATRA may contribute to the pathology of chronic arthritic disease by potentially causing increased growth of the joint-destroying pannus.
Gitter
B D
BD
Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis, Indiana 46285-0403.
Koehneke
E M
EM
D002455:Cell Division / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D004357:Drug Synergism; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000032:analysis; D017472:Receptors, Interleukin-1; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007375:Interleukin-1; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D014212:Tretinoin; D015232:Dinoprostone