Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor
Gillian S. Ashcroft, … , Sharon M. Wahl, Toshinori Nakayama
Gillian S. Ashcroft, … , Sharon M. Wahl, Toshinori Nakayama
Published May 1, 2003
Citation Information: J Clin Invest. 2003;111(9):1309-1318. https://doi.org/10.1172/JCI16288.
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Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor

Abstract

Characteristic of both chronic wounds and acute wounds that fail to heal are excessive leukocytosis and reduced matrix deposition. Estrogen is a major regulator of wound repair that can reverse age-related impaired wound healing in human and animal models, characterized by a dampened inflammatory response and increased matrix deposited at the wound site. Macrophage migration inhibitory factor (MIF) is a candidate proinflammatory cytokine involved in the hormonal regulation of inflammation. We demonstrate that MIF is upregulated in a distinct spatial and temporal pattern during wound healing and its expression is markedly elevated in wounds of estrogen-deficient mice as compared with intact animals. Wound-healing studies in mice rendered null for the MIF gene have demonstrated that in the absence of MIF, the excessive inflammation and delayed-healing phenotype associated with reduced estrogen is reversed. Moreover, in vitro assays have shown a striking estrogen-mediated decrease in MIF production by activated murine macrophages, a process involving the estrogen receptor. We suggest that estrogen inhibits the local inflammatory response by downregulating MIF, suggesting a specific target for future therapeutic intervention in impaired wound-healing states.

Authors

Gillian S. Ashcroft, Stuart J. Mills, KeJian Lei, Linda Gibbons, Moon-Jin Jeong, Marisu Taniguchi, Matthew Burow, Michael A. Horan, Sharon M. Wahl, Toshinori Nakayama

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Figure 6

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Murine macrophage MIF production, by LPS-activated cells, is decreased w...
Murine macrophage MIF production, by LPS-activated cells, is decreased with concurrent estrogen treatment (a). Results represent means ± SEM (n = 10 for each group) *P < 0.05, **P < 0.01, all compared with control media plus LPS-activated macrophages (C+). LPS activation significantly increased MIF production as compared with control media alone (P < 0.05). (b) Immunostaining illustrates that monocytes (CD14+ cells) express both ER-α and ER-β isoforms. The far right panel of b represents a merged image of all three panels (ER-α, ER-β, and CD14). Scale bar represents 10 μm. (c) LPS treatment increases MIF levels from wild-type murine cells and is inhibited by estrogen. In the absence of ER-α (ER-α null), estrogen fails to downregulate LPS-induced MIF production. LPS significantly increased MIF in both wild-type and ER-α null macrophages (P < 0.05). Seeding density of cells is three times higher than in Figure 5a. Results represent means ± SEM (n = 5 for each group, *P < 0.05 as compared with LPS-activated cells). (d) MCF7 ER-expressing cells transfected with a MIF promoter–luciferase reporter construct showed increased activity after LPS activation (a). Estrogen (10–8 M) inhibited this activity. Transfection with pGL3 basic plasmid acted as a negative control (pGL3–ve), and pGL3 control plasmid as a positive control (pGL3+ve). Results represent means ± SEM (n = 3–5 for each group, *P < 0.05 as compared with LPS-activated cells). (e) MCF7 ER-expressing cells transfected with a MIF promoter–luciferase reporter construct showed inhibition of LPS-activated MIF production by estrogen and estrogen agonists (PPT, HPTE) and reversal of estrogenic effects by ER antagonist (ICI). Results represent means ± SEM for three experiments (*P < 0.05 as compared with LPS-activated cells). C, control media alone; +, + LPS treatment for 6 hours; E8, 10–8 M estrogen; E9, 10–9 M estrogen; E10, 10–10 M estrogen; E11, 10–11 M estrogen; RLU, relative light units.