TY - JOUR
T1 - SOCS3 negatively regulates the gp130-STAT3 pathway in mouse skin wound healing
AU - Zhu, Bing Mei
AU - Ishida, Yuko
AU - Robinson, Gertraud W.
AU - Pacher-Zavisin, Margit
AU - Yoshimura, Akihiko
AU - Murphy, Philip M.
AU - Hennighausen, Lothar
N1 - Funding Information:
We would like to thank Drs Angel Ramirez (CIEMAT, Madrid, Spain) and Robert Smart (North Carolina State University, Raleigh, NC) for providing K5-Cre transgenic mice and Dr Colin Stewart for providing gp130 floxed mice. We also thank Amy Rosenthal, a summer student, for contributing to data analysis of wound healing. This work was supported by the intramural research programs of NIDDK and NIAID, NIH.
PY - 2008/7
Y1 - 2008/7
N2 - 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.
AB - 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.
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U2 - 10.1038/sj.jid.5701224
DO - 10.1038/sj.jid.5701224
M3 - Article
C2 - 18185532
AN - SCOPUS:45349102930
SN - 0022-202X
VL - 128
SP - 1821
EP - 1829
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 7
ER -