Background: Regardless of its involvement in either wound healing or excessive fibrosis, the interstitial fibroblast can now be considered an important early participant in inflammatory responses. Although it is recognized that certain immune cells and proinflammatory mediators are intricately linked to fibrotic disease, little is presently known about the manner in which these mediators and cells are orchestrated to a fibrotic finale. Experimental studies have shown that interstitial fibroblasts are capable of participating in an inflammatory response by promoting direct fibroblast-to-immune cell communication and/or modulating the release of soluble mediators that are mutually recognized by both types of cells.
Methods: Primary cultures of murine fibroblasts were recovered from either normal tissue or tissue undergoing a cell-mediated inflammatory response. These stromal cells were assessed for the expression of various cytokines and chemokines indicative of a type 1 or type 2 response. In addition, the fibroblasts were co-cultured with mononuclear cells to assess the cell-to-cell communication.
Results: Fibroblasts recovered from different cell-mediated inflammatory responses demonstrated a dramatic alteration in their cytokine profile. Fibroblasts recovered from the type 2 immune response produced high levels of monocyte chemotactic protein-1 (MCP-1), as compared to the normal fibroblasts and fibroblasts recovered from the type 1 lesion. Mononuclear cells co-cultured with fibroblasts induced a contact-dependent expression of elevated levels of chemokines, especially the macrophage-derived MIP-1 alpha. Thus, both fibroblasts themselves and fibroblasts co-cultured with immune-inflammatory cells have the ability to participate in the maintenance of an inflammatory response via the expression of chemokines.
Conclusions: Our laboratory and others have addressed the role of chemotactic cytokines or chemokines in the fibrotic process, and have demonstrated that fibroblasts are capable of modulating the activation of various immune cells that have been implicated in fibrotic disease. In addition, the interstitial fibroblast is capable of regulating its own behavior within the interstitial environment via the expression of chemokines and chemokine receptors. Thus, novel strategies aimed at preventing fibrotic disease will likely need to address the early engagement of inflammatory cells by fibroblasts, and possibly modulate the ability of fibroblasts to generate and/or recognize profibrotic signals supplied by chemokines.