Interleukin-6 (IL-6) modulates migration and matrix metalloproteinase function in dermal fibroblasts from IL-6KO mice

BACKGROUND: Interleukin-6-deficient (IL-6KO) mice display significantly delayed cutaneous wound healing characterized by decreased re-epithelialization, granulation tissue and wound closure. Dermal fibroblasts are one of the principal cell types found in granulation tissue and mediate numerous processes during healing. OBJECTIVES: To investigate the effects that IL-6 might have on granulation tissue formation and fibroblast motility. As fibroblast motility is associated with matrix metalloproteinase (MMP) activity, the expression of MMP-2 and the tissue inhibitors of metalloproteinase (TIMP)-1 and -2 were assessed. METHODS: Punch biopsies (4 mm) were performed in the skin of IL-6KO and C57BL/6 mice. The expression of MMP-2, TIMP-1 and -2 in wound tissue was monitored over time. Cellular infiltration and granulation tissue formation was monitored by subcutaneous implantation of polyvinyl alcohol (PVA) sponges. A free-floating collagen lattice model was also used to investigate the direct effects of IL-6 treatment on isolated IL-6KO fibroblasts. The expression of MMP-2, and the inhibitors TIMP-1 and -2, were assessed via real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: IL-6KO wounds showed impaired granulation tissue formation 5 days postwounding and fewer fibroblasts had populated the PVA matrices 7 days after implantation in IL-6KO mice compared with wild-type C57BL/6. The mRNA and protein expression of MMP-2 and TIMP-2 mRNA was increased in IL-6KO mice compared with wild-type mice beyond 1 day postwounding, while the expression of TIMP-1 mRNA was transiently higher in IL-6KO only 3 days postwounding. Treatment of collagen lattices with various concentrations of rmIL-6 again showed a dose-response decrease in mRNA and protein expression of MMP-2 and TIMP-2 protein expression, compared with saline control, while TIMP-1 did not appear to be significantly modulated. CONCLUSIONS: These results indicate that IL-6 influences the function of fibroblasts in wounds, and one mechanism of this regulation may be through the modulation of MMP-2 and TIMP proteins.