Endogenous TNFa Suppression of Migration of Corneal Epithelium

Abstract

Purpose:: To evaluate the role of endogenous tumor necrosis factor a (TNFa) in epithelial healing of a mouse cornea.

Methods:: Healing of debridement of central corneal epithelium was examined in TNFa-null mice. Histology and immunohistochemistry were conducted to examine the level of inflammation in the stroma. Healing of central epithelial defect was also observed in organ-culture with or without neutralizing antibody against either TNFa or transforming growth factor b1 (TGFb1). Cell culture of immortalized corneal epithelial cell line was employed to examine the role of TNFa and TGFb1 on cell migration and cell signaling.

Results:: Loss of TNFa promoted re-epithelialization of debridement in vivo. Lacking TNFa did not significantly affect the degree of inflammation in the epithelium-debrided stroma before 24 hrs, but inflammation was more marked in a WT stroma beneath the defected epithelium at 24 hrs. In an organ-culture system also healing of an epithelial defect was promoted by the loss of TNFa. A neutralizing antibody against TNFa also promoted closure of epithelial defect of organ-cultured WT mouse corneas. Anti-TGFb neutralizing antibody reversed facilitation of epithelial healing in KO corneas in organ-culture. In cell culture of corneal epithelial cell line adding TNFa suppresses activation of p38 signal and cell migration, but not Smad2 activation, upon TGFb1 exposure.

Conclusions:: TNFa inhibits migration of corneal epithelial cells via counteraction of TGFb/p38 signal.

Keywords: growth factors/growth factor receptors • signal transduction • wound healing