The influence of interleukin-4 on ligament healing.

Despite a complex cascade of cellular events to reconstruct the damaged extracellular matrix, ligament healing results in a mechanically inferior scarred ligament. During normal healing, granulation tissue expands into any residual normal ligamentous tissue (creeping substitution), resulting in a larger region of healing, greater mechanical compromise and an inefficient repair process. To control creeping substitution and possibly enhance the repair process, the antiinflammatory cytokine, interleukin-4 (IL-4), was administered to rats before and after rupture of their medial collateral ligaments. In vitro experiments showed a time-dependent effect on fibroblast proliferation after IL-4 treatment. In vivo treatments with IL-4 (100 ng/mL IV) for 5 days resulted in decreased wound size and type III collagen and increased type I procollagen, indicating a more regenerative early healing in response to the IL-4 treatment. However, continued treatment of IL-4 to day 11 antagonized this early benefit and slowed healing. Together, these results suggest that IL-4 not only influences the macrophages and T lymphocytes but also stimulates fibroblasts associated with the proliferative phase of healing in a dose-, cell-, and time-dependent manner. Although treatment significantly influenced healing in the first week after injury, IL-4 alone was unable to maintain this early regenerative response.