IL-6 Modulates Alpha-Smooth Muscle Actin Expression in Dermal Fibroblasts from IL-6-Deficient Mice

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 ( α -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 α -SMA mRNA was found to be increased in wounds of IL-6KO mice up to 48hours post wounding, but decreased below wild-type levels by 72hours. Recombinant IL-6 treatment of IL-6KO dermal fibroblasts showed an induction of α -SMA mRNA and protein peaking at 1ng/ml cytokine, but declining at higher concentrations. Actinomycin-D treatment of fibroblast cultures indicated that recombinant mouse IL-6 (rmIL-6) induction of α -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 α -SMA expression is dysregulated in IL-6KO mice. The expression of α -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.