Fibrotic disease and the TH1/TH2 paradigm

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Abstract
The tissue-repair process involves two distinct stages: a regenerative phase, in which injured cells are replaced by cells of the same type, leaving no lasting evidence of damage; and a phase known as fibroplasia or fibrotic scarring, in which connective tissue replaces normal parenchymal tissue. Despite their obvious aetiological and clinical distinctions, most fibrotic diseases share a common paradigm characterized by a persistent inflammatory stimulus and lymphocyte–monocyte interactions that generate fibrogenic cytokines, which stimulate the deposition of connective tissue. However, fibrosis is not always linked with robust inflammation, indicating that the mechanisms regulating fibrogenesis are distinct. Experiments using knockout mice have shown that fibrogenesis is associated with 'anti-inflammatory' T helper 2 (TH2) CD4+ T-cell responses, whereas pro-inflammatory TH1-cell responses are inhibitory. Interleukin-4 (IL-4), IL-5 and IL-13, the signature TH2 cytokines, have distinct roles in the regulation of tissue remodelling and fibrosis. However, results from various experimental models indicate that IL-13 is the master regulator. Transforming growth factor-β1 (TGF-β1) has been linked with the fibrosis that occurs in several diseases. Macrophages are an important source of TGF-β1, which directly activates collagen deposition by fibroblasts. IL-13-secreting CD4+ TH2 cells regulate fibrogenesis directly by stimulating collagen synthesis by fibroblasts and indirectly by promoting TGF-β1 production by macrophages. IL-13 induces the production of, and activates, TGF-β1, by upregulating the expression of matrix metalloproteinases that cleave the latency-associated peptide. Chemokines are strong leukocyte chemoattractants that cooperate with pro-fibrotic cytokines by recruiting macrophages and other effector cells to sites of tissue damage. CC-chemokine ligand 3 (CCL3; also known as macrophage inflammatory protein 1α) and several related CC-chemokines have been identified as essential pro-fibrotic mediators. Macrophages and fibroblasts operate as key effector cells in the pathogenesis of fibrosis. The preferential activation of arginase 1 versus nitric-oxide synthase 2 in these cells might explain the potent pro-fibrotic activity of IL-13 and the antifibrotic activity of interferon-γ. An attractive antifibrotic strategy would exploit the natural suppressive mechanisms of the host, which include regulatory T cells, IL-10 and the IL-13 decoy receptor. Because of its ability to activate the wound-healing response, it might be more accurate to describe the TH2-cell response as an 'adaptive tissue-healing mechanism', instead of as a simple counter-regulatory system for the TH1-cell response.