Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor.
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.
Ashcroft
Gillian S
GS
School of Biological Sciences, University of Manchester, Manchester, United Kingdom. gillian.s.ashcroft@man.ac.uk
Mills
Stuart J
SJ
Lei
KeJian
K
Gibbons
Linda
L
Jeong
Moon-Jin
MJ
Taniguchi
Marisu
M
Burow
Matthew
M
Horan
Michael A
MA
Wahl
Sharon M
SM
Nakayama
Toshinori
T
D000818:Animals; D015536:Down-Regulation / Q000502:physiology*; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D004967:Estrogens / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010052:Ovariectomy; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
D004967:Estrogens; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D011960:Receptors, Estrogen; D016212:Transforming Growth Factor beta