Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor

J Clin Invest. 2003 May;111(9):1309-18. doi: 10.1172/JCI16288.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Down-Regulation / physiology*
  • Epidermal Cells
  • Epidermis / metabolism
  • Epidermis / pathology
  • Estrogens / genetics
  • Estrogens / metabolism*
  • Female
  • Humans
  • Lipopolysaccharides / pharmacology
  • Macrophage Migration-Inhibitory Factors / genetics
  • Macrophage Migration-Inhibitory Factors / metabolism*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Ovariectomy
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Transforming Growth Factor beta / metabolism
  • Wound Healing / physiology*


  • Estrogens
  • Lipopolysaccharides
  • Macrophage Migration-Inhibitory Factors
  • Receptors, Estrogen
  • Transforming Growth Factor beta