title: IL-6 modulates alpha-smooth muscle actin expression in dermal fibroblasts from IL-6-deficient mice.
abstract: IL-6 deficient (IL-6KO) mice display significantly delayed cutaneous wound closure. Myofibroblasts are the primary mediators of wound closure, and alpha-smooth muscle actin (alpha-SMA) is a marker of fibroblast differentiation to the myofibroblast phenotype. Wounds from IL-6KO, and wild-type mice were collected up to 6 days following wounding. Expression of alpha-SMA mRNA was found to be increased in wounds of IL-6KO mice up to 48 hours post wounding, but decreased below wild-type levels by 72 hours. Recombinant IL-6 treatment of IL-6KO dermal fibroblasts showed an induction of alpha-SMA mRNA and protein peaking at 1 ng/ml cytokine, but declining at higher concentrations. Actinomycin-D treatment of fibroblast cultures indicated that recombinant mouse IL-6 (rmIL-6) induction of alpha-SMA mRNA appeared to be primarily transcriptionally regulated, and extracellular signal-regulated kinase 1/2 kinase, but not signal transducers and activators of transcription 3 was readily phosphorylated in rmIL-6 treated IL-6KO fibroblasts. A dose-response increase in the mRNA expression of the IL-6R signaling inhibitor protein suppressors of cytokine signaling (SOCS) 3 was also noted in rmIL-6-treated IL-6KO fibroblasts. These data indicate that alpha-SMA expression is dysregulated in IL-6KO mice. The expression of alpha-SMA induced by rmIL-6 in fibroblasts from IL-6KO mice appears to be transcriptionally modulated, dependent on JAK1 kinase, and possibly downregulated as a result of increased SOCS3 expression.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73117, USA. randy-gallucci@ouhsc.edu
authors.forename: Randle M
authors.initials: RM
authors.lastname: Gallucci
authors.forename: Eric G
authors.initials: EG
authors.lastname: Lee
authors.forename: James J
authors.initials: JJ
authors.lastname: Tomasek
mesh_terms: D000199:Actins / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D015850:Interleukin-6 / Q000502:physiology*; D053613:Janus Kinase 1; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D012867:Skin / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology; D015533:Transcriptional Activation; D014945:Wound Healing
chemical_list: D000199:Actins; D015850:Interleukin-6; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D048049:Extracellular Signal-Regulated MAP Kinases