title: Interleukin-6 production in human fibroblasts derived from periodontal tissues is differentially regulated by cytokines and a glucocorticoid.
abstract: Interleukin-6 (IL-6) is thought to be a major mediator of the host's defense against infection, and it regulates immune responses in inflamed tissue. In this study, we investigated the regulation of IL-6 production in human gingival fibroblasts (HGF) and human periodontal ligament fibroblasts (HPLF). Pro-inflammatory cytokines including interleukin (IL)-1 alpha, IL-1 beta and tumor necrosis factor (TNF)-alpha stimulated IL-6 production in HGF and HPLF in a time- and dose-dependent manner. This IL-1 alpha, IL-1 beta, or TNF-alpha-induced IL-6 production was enhanced, but the cAMP accumulation they induced was inhibited by the addition of indomethacin. This result suggests that endogenous prostaglandin E2 (PGE2) partially inhibits IL-1 or TNF-alpha-induced IL-6 production and that the enhancement of IL-6 production by IL-1 or TNF-alpha may not be caused through endogenous PGE2-induced cAMP-dependent pathway. Dexamethasone (DEX), a glucocorticoid which is a inhibitor of nuclear factor kappa B (NF-kappa B activation, markedly inhibited IL-1 (alpha or beta) or TNF-alpha-induced IL-6 production; so this production may be partially mediated through NF-kappa B. IL-1 (alpha or beta) and TNF-alpha enhanced IL-6 production synergistically. IL-6 production in HGF or HPLF stimulated with IL-1 beta was augmented by the addition of interferon (IFN)-gamma, but was slightly suppressed by the addition of IL-4. Endogenous IL-6 enhanced IL-1 (alpha or beta)-induced IL-6 production in the presence of IL-6 soluble receptor (IL-6sR). Accordingly, in inflamed periodontal tissues, gingival fibroblasts and periodontal ligament fibroblasts stimulated with pro-inflammatory cytokines such as IL-1 or TNF-alpha, may produce IL-6, and this production can be differentially modulated by endogenous PGE2, IL-6sR, T cell-derived cytokines such as IFN-gamma or IL-4, and glucocorticoids.
authors.affiliation: Department of Periodontics, Showa University Dental School, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Okada
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: K
authors.initials: K
authors.lastname: Mugikura
authors.forename: Y
authors.initials: Y
authors.lastname: Okamatsu
authors.forename: S
authors.initials: S
authors.lastname: Hanazawa
authors.forename: S
authors.initials: S
authors.lastname: Kitano
authors.forename: K
authors.initials: K
authors.lastname: Hasegawa
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016207:Cytokines / Q000008:administration & dosage / Q000494:pharmacology*; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000276:immunology*; D005881:Gingiva / Q000166:cytology / Q000276:immunology*; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000008:administration & dosage / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010513:Periodontal Ligament / Q000166:cytology / Q000276:immunology*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000242:Cyclic AMP; D016207:Cytokines; D003907:Dexamethasone; D015232:Dinoprostone; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D007213:Indomethacin; D007371:Interferon-gamma; D007375:Interleukin-1; D015847:Interleukin-4; D015850:Interleukin-6; D016328:NF-kappa B; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors