Assessment of the involvement of the macrophage migration inhibitory factor (MIF)-glucocorticoid regulatory dyad in MMP-2 expression during periodontitis

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine and counterregulator 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.