Enhancement of gingival inflammation induced by synergism of IL-1^|^beta; and IL-6

Abstract

Internleukin-1 (IL-1) and IL-6 are the most potent proinflammatory cytokines being involved in inflammatory diseases such as periodontitis. The objective of this study was to examine the synergistic effects of IL-1β and IL-6 on gingival inflammation by targeting cultured human gingival fibroblasts (HGFs). HGFs were treated with IL-1β or IL-6/soluble IL-6R (sIL-6R), and total RNA and total cell lysate were collected to examine expression of gp130 known as a signal transducer of IL-6 using qRT-PCR and Western blotting. IL-1β-mediated IL-6 productivity in HGFs was examined using ELISA method. Likewise, after HGFs and THP-1 macrophages were treated with IL-1β, TNF-α and IL-6, sIL-6R productivity was examined. Next, HGFs were treated with IL-6/ sIL-6R after pretreatment of IL-1β, and the intracellular signals were examined using Western blotting. Finally, various mRNA/protein expressions in HGFs treated with IL-6/sIL-6R after pretreatment of IL-1β were examined using qRT-PCR and ELISA method. IL-1β increased significantly both gp130 and IL-6 expression in HGFs. IL-6 increased significantly sIL-6R production in THP-1 macrophages but not HGFs. Co-stimulation with IL-1β and IL-6/sIL-6R induced dramatically the phosphorylation of Stat3, ERK and JNK in HGFs. Interestingly, expression of various inflammation-related molecules such as MMP-1, MCP-1, IL-1ra, bFGF and VEGF were enhanced by co-stimulation with IL-1β and IL-6/sIL-6R in HGFs. Gingival inflammation is regulated by HGFs affected by both IL-1β and IL-6/sIL-6R synergistically through induction of gp130 expression, resulting in progression of periodontitis.

High Glucose-Mediated Cytokine Regulation in Gingival Fibroblasts and THP-1 Macrophage: a Possible Mechanism of Severe Periodontitis with Diabetes

“…Furthermore, we showed previously that IL-6 binding to HGFs increases significantly in the presence of sIL-6R [20]. Considering the possible source of sIL-6R in periodontitis lesions, we reported that sIL-6R production was induced by IL-6 and CPT in THP-1 macrophages [7,21]. Importantly, we showed that CPT-mediated induction of sIL-6R inhibited significantly in THP-1 macrophages by TACE specific inhibitor, TAPI-1 (Fig.…”

“…In addition, TIMPs are considered to be important molecules to regulate the actions of MMPs [25], and a disturbed balance of MMPs and TIMPs should be involved in the progression of periodontitis [26]. IL-1β and IL-6 may be responsible to the tissue destruction by increasing MMPs from HGFs [21]. In view of severe periodontitis in diabetic patients, therefore, we examined the effects of HG on IL-1β or IL-6-induced MMP-1 and TIMP-1 in HGFs.…”

Effects of miR-223 on expression of IL-1β and IL-6 in human gingival fibroblasts

“…Fibroblasts constitutively express a low level of IL-6. Furthermore, IL-1 and TNF-α synergistically enhance the production of IL-6 by fibroblasts (31)(32)(33). IL-1β and TNF-α induce NF-κB expression, and then NF-κB subsequently controls the expression of IL-1β, IL-6 and TNF-α (34)(35)(36).…”

Inflammatory Bone Loss in Experimental Periodontitis Induced by Aggregatibacter actinomycetemcomitans in Interleukin-1 Receptor Antagonist Knockout Mice

“…IL-1Ra levels in gingival crevicular fluid (GCF) are negatively correlated with disease severity in chronic periodontitis patients (18), while IL-1Ra levels in moderate and deep pockets from patients with aggressive periodontitis were lower than those at control sites (19). In contrast, IL-1Ra mRNA expression was found to be upregulated with IL-1␤ or the IL-6/soluble IL-6 receptor (sIL-6R) complex in inflamed human gingival tissue (20). Peripheral blood mononuclear cells from patients with generalized aggressive periodontitis exhibited higher levels of IL-1Ra and IL-10 than those from healthy controls with or without LPS stimulation (21).…”