title: Epithelial overexpression of SOCS-3 in transgenic mice exacerbates wound inflammation in the presence of elevated TGF-beta1.
abstract: The suppressor of cytokine signaling (SOCS)-3 has been shown to impair proliferation and migration of keratinocytes. To assess the functional dependency among wound inflammation, SOCS-3 induction in keratinocytes, and the outcome of healing, we generated a transgenic mouse that specifically overexpresses SOCS-3 in keratinocytes. Acute wound healing in transgenic mice was severely impaired. Keratinocyte-specific overexpression of SOCS-3 led to atrophied wound-margin epithelia and augmented the inflammatory response of wound keratinocytes by an increase in chemokine (MIP-2) and inflammatory enzyme (COX-2 and iNOS) expression. In addition, wound tissue of transgenic mice showed a prolonged persistence of neutrophils and macrophages. Remarkably, impaired wounds showed elevated levels of transforming growth factor (TGF)-beta1, which appeared to interfere with healing, as its neutralization markedly improved wound closure in transgenic mice. Interestingly, administration of a TGF-beta-neutralizing antibody increased wound inflammation in nontransgenic mice but not in transgenic littermates. This study suggests that SOCS-3-driven disturbances in wound keratinocytes are sufficient to induce inflamed wound conditions that resemble characteristics of chronic wounds in mice.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Linke
authors.forename: Itamar
authors.initials: I
authors.lastname: Goren
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bösl
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.forename: Stefan
authors.initials: S
authors.lastname: Frank
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D002908:Chronic Disease; D003872:Dermatitis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D015870:Gene Expression / Q000502:physiology; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000473:pathology; D012867:Skin / Q000293:injuries / Q000473:pathology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
chemical_list: D000906:Antibodies; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053773:Transforming Growth Factor beta1