Interaction between macrophages, TGF-beta1, and the COX-2 pathway during the inflammatory phase of skeletal muscle healing after injury.

Inflammation, an important phase of skeletal muscle healing, largely involves macrophages, TGF-beta1, and the COX-2 pathway. To improve our understanding of how these molecules interact during all phases of muscle healing, we examined their roles in muscle cells in vitro and in vivo. Initially, we found that depletion of macrophages in muscle tissue led to reduced muscle regeneration. Macrophages may influence healing by inducing the production of TGF-beta1 and PGE2 in different muscle cell types. We then found that the addition of TGF-beta1 induced PGE2 production in muscle cells, an effect probably mediated by COX-2 enzyme. It was also found that TGF-beta1 enhanced macrophage infiltration in wild-type mice after muscle injury. However, this effect was not observed in COX-2(-/-) mice, suggesting that the effect of TGF-beta1 on macrophage infiltration is mediated by the COX-2 pathway. Furthermore, we found that PGE2 can inhibit the expression of TGF-beta1. PGE2 and TGF-beta1 may be involved in a negative feedback loop balancing the level of fibrosis formation during skeletal muscle healing. In conclusion, our results suggest a complex regulatory mechanism of skeletal muscle healing. Macrophages, TGF-beta1, and the COX-2 pathway products may regulate one another's levels and have profound influence on the whole muscle healing process. (c) 2007 Wiley-Liss, Inc.