Enhancement of macrophage migration inhibitory factor (MIF) expression in injured epidermis and cultured fibroblasts

Abstract

After the cDNA of human macrophage migration inhibitory factor (MIF) was cloned in 1989, this protein has been re-evaluated as a pro-inflammatory cytokine, pituitary hormone and glucocorticoid-induced immunoregulatory protein. We previously reported the expression of MIF in the basal cell layers of the epidermis, but its pathophysiological function in the skin has not been well understood. In this study, we examined the expression of MIF during the wound healing of rat skin injured by excision. Reverse transcription-polymerase chain reaction in combination with Southern blot analysis revealed that the increase of MIF mRNA expression was biphasic. The maximum peaks were observed at 3 and 24 h after the injury. Similarly, maximal increases of the serum MIF level were observed at 3 and 24 h after the injury. Immunohistochemical analysis at 12 h after injury demonstrated enhanced expression of MIF protein in the whole epidermal lesion of the wound tissue. By the Boyden chamber assay, we demonstrated that MIF had a chemotactic effect on freshly prepared keratinocytes from rat skin. Additionally, cultured fibroblasts from the skin wound lesion secreted a higher amount of MIF in response to lipopolysaccharide compared to those of the normal skin. Furthermore, administration of anti-MIF antibodies induced a delay of wound healing in vivo. Taken together, these results suggest that MIF contributes to the wound healing process of skin tissue.

A novel DNA vaccine-targeting macrophage migration inhibitory factor improves the survival of mice with sepsis

“…We examined the wound healing ability of mice at 6 weeks after vaccination, and found no statistical difference between MIF/TTX group and control group. Abe et al 33 previously reported that the administration of anti-MIF antibody resulted in significantly delayed wound healing in C57BL6 mice; however, we failed to show such significant difference, although MIF/TTX group tended to show slight delay in wound healing. Concerning this discrepancy, it is known that the wound healing ability of mice are influenced by their strain, and BALB/c mice generally tend to show delayed wound healing compared with C57BL6.…”

Macrophage migration inhibitory factor (MIF) promotes fibroblast migration in scratch‐wounded monolayers in vitro

“…In summary, judging from the previous data by the Ashcroft and Nishihira groups [13][14][15][16] in conjunction with our current study, we predict that MIF contributes to both the inflammatory and migration/proliferation phases of wound healing. We propose the following chronology of events involving MIF.…”

“…Estrogen-mediated down-regulation of MIF and protection from MIF-dependent inflammatory processes was recently confirmed in a model of colon inflammation [30]. On the other hand, Abe and colleagues observed that an upregulation of MIF in skin wounds of rats was accompanied by an accelerating effect of MIF on the wound healing process of skin tissue [15]. On first sight contradictory, these observations may suggest that MIF influences more than one mechanism contributing to wound healing outcome.…”

“…These observations went along with increased serum and wound levels of MIF over age and a down-regulation of MIF by estrogen in vivo. While these studies have implicated MIF in the attenuation of wound healing in the absence of estrogen, Abe et al noticed that a biphasic induction of MIF during wound healing of rat skin injured Abbreviations: CXCR, CXC chemokine receptor; GPCR, G-proteincoupled receptor; HFDFs, human foreskin dermal fibroblasts; MEFs, mouse embryonic fibroblasts; MIF, macrophage migration inhibitory factor; rMIF, recombinant human MIF; wt, wild-type; wtMEFs, wildtype MEFs by excision was accompanied by an accelerating effect of MIF on the wound healing process of skin tissue [15]. When comparing excision wounds from the dorsal skin of MIF À/À mice with those of wild-type animals (MIF +/+ ), healing was significantly delayed in MIF À/À mice, suggesting that MIF is crucial in accelerating cutaneous wound healing [16].…”

The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting

“…2). The primary focus of MIF research has been in the context of its role in immunological function, and studies that used pure recombinant MIF and MIF-specific antibodies have established a role of MIF in the pathogenesis of septic shock (3), inflammatory arthritis (4), glomerulonephritis (5), allograft rejection (6), and wound repair (7). At the cellular level, MIF has been reported to antagonize the action of glucocorticoids and to promote the production of proinflammatory mediators (reviewed in ref.…”