1. ¹Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
2. ²Laboratory of Molecular Immunology, Molecular Signaling Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
3. ³Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

Correspondence: Dr Lothar Hennighausen, Laboratory of Genetics and Physiology, NIDDK, National Institutes of Health, Building 8, Room 101, 8 Center Drive, Bethesda, Maryland 20892, USA. E-mail: lotharh@mail.nih.gov

Received 31 May 2007; Revised 5 November 2007; Accepted 11 November 2007; Published online 10 January 2008.

Abstract

Proliferation and differentiation of keratinocytes during wound healing are regulated by cytokines and chemokines, which are secreted by resident and inflammatory cells and activate the transcription factor signal transducer and activator of transcription (STAT)3. However, it is not clear to what extent STAT3 in keratinocytes is activated by gp130-containing receptors. We addressed this question genetically by deleting the suppressor of cytokine signaling (SOCS)3, a negative regulator of gp130-mediated STAT3 activation. Socs3 alleles flanked by loxP sites were deleted in mice with either an MMTV-Cre or K5-Cre transgene. While both transgenes are active in keratinocytes, the MMTV-Cre deletes floxed genes also in immune cells. Deletion of Socs3 using the MMTV-Cre transgene resulted in aberrant STAT3 activation, impaired wound healing, prolonged secretion of chemokines, a hyperproliferative epidermis, and neutrophil infiltration into wounds. Simultaneous deletion of the Socs3 and gp130 genes restored normal wound healing. Moreover, deletion of Socs3 only in keratinocytes caused impaired wound healing. These results demonstrate that wound healing is controlled in keratinocytes by the gp130–SOCS3–STAT3 pathway and an imbalance of this pathway results in delayed wound healing.