Assessment of the involvement of the macrophage migration inhibitory factor–glucocorticoid regulatory dyad in the expression of matrix metalloproteinase‐2 during periodontitis

Abstract

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine and counter-regulator of endogenous glucocorticoids. It is implicated in acute and chronic inflammatory diseases. This study investigated the role of the MIF-glucocorticoid (GC) regulatory dyad in MMP2 expression and release during periodontitis in vivo and in vitro. In a MIF knockout (KO) mouse model of ligature-induced periodontitis, gingival tissues and blood were collected and analyzed for levels of IL6, MIF, MMP2 and corticosterone. In addition, human gingival fibroblasts (HGF) were tested for production of IL6 and MMP2 after stimulation with hydrocortisone (HC), MIF, TNF-α or Fusobacterium nucleatum, a pathogen known to elicit immune responses during periodontitis. Wild type (WT) mice showed a local and systemic increase of MIF levels during inflammation, which was confirmed by increased local IL6 concentrations. Systemic GC were reduced in WT and MIF KO mice during inflammation with overall lower concentrations in MIF KO mice. In vivo and in vitro, MMP2 production was not dependent on MIF or inflammatory stimuli, but was inhibited by HC. Therefore, MIF does not appear to stimulate MMP2 expression in the gingival tissues, whereas GC upregulate MIF and downregulate MMP2. Our findings further suggest that MIF may regulate systemic GC levels.

Elevated Expression of Macrophage Migration Inhibitory Factor Promotes Inflammatory Bone Resorption Induced in a Mouse Model of Periradicular Periodontitis

“…1). These data indicate that MIF mRNA expression appeared to be upregulated in the periradicular lesion induced in mice, corresponding to our previously published report, demonstrating that expression of MIF mRNA as well as its protein level are elevated in the experimental periodontitis induced in mice by ligature attachment (21).…”

“…Although a plethora of studies has demonstrated the pathogenic roles of MIF, a variety of medical complications, such as heart failure, type two diabetes, and rheumatoid arthritis in the past decades (48)(49)(50)(51), and MIF's role in the bone pathophysiology remains controversial. Our group and others reported that MIF promotes osteoclastogenesis in vitro and upregulates the pathogenic bone resorption in various mouse models of osteolytic lesions (16,19,21). However, one research group reported that MIF deficiency inhibits both osteoclast and osteoblast activities without changing the numbers of osteoblasts or osteoclasts and reduces the bone mass in the context of homeostatic bone remodeling (42,52).…”

“…We recently found that locally produced MIF is engaged in chemoattraction of osteoclast precursors (OCPs) to the inflammatory bone resorption site in the osteolytic lesions induced by bone-cement wear debris in a CXCR4-dependent manner, whereas SDF-1 (CXCL12), the other chemokine that binds to CXCR4, facilitates the chemotaxis of OCPs in the healthy bone-remodeling site (16). Pathogenic engagement of MIF is implicated in inflammatory bone destructive diseases, such as rheumatoid arthritis (19) and marginal periodontitis (20,21). Nonetheless, although Liu and Peng (22) reported the coexpression of MIF and RANKL in the periradicular lesion induced in rats, the functional role of MIF in alveolar bone resorption in the periapical periodontitis has not yet been addressed.…”

Periodontal Disease in Diabetes Mellitus: A Case–Control Study in Smokers and Non-Smokers

“…Excessive inflammation of the periodontal tissues (periodontitis) is the hallmark feature of PD. In PD, bacteria in the oral biofilm interfere with the body's defense mechanisms, activating the immune system which in turn results in inflammation and the immune response [17,18]. The levels of C-reactive protein, prostaglandin E 2 interleukin-1beta, and tumor necrosis factor alpha increase in PD [19].…”

Macrophage Migration Inhibitory Factor Levels in Gingival Crevicular Fluid, Saliva, and Serum of Chronic Periodontitis Patients

“…Some studies have identified MIF overexpression in GCF from subjects with gingivitis [23], in gingival tissue from subjects with CP, in serum and tissue of mice with induced periodontitis [15, 30]. In addition, it has been described that MIF gene polymorphism ( MIF -173 G/C) increased the risk of CP [31].…”