FIBROTIC DISEASE AND THE TH1/TH2 PARADIGM

Interleukin-13 (IL-13) promotes collagen production by three distinct but possibly overlapping mechanisms. a | IL-13 is produced by activated CD4+ T helper 2 (TH2) cells and stimulates the production of latent transforming growth factor-β (TGF-β) by macrophages. The activation of latent TGF-β is important for both its physiological and pathological actions on target cells, such as fibroblasts. Following the intracellular processing of prepro-TGF-β to its latent complex, the latent TGF-β is secreted and then anchored to the macrophage membrane through thrombospondin-1 bound to its receptor, CD36. Activation of TGF-β might be mediated by plasmin/serine protease- and/or matrix metalloproteinase 9 (MMP9)-dependent mechanisms. After the latency-associated peptide (LAP) is cleaved, TGF-β is free to bind and activate TGF-β receptors (TGF-βRs) expressed by fibroblasts. In this pathway, the fibrogenic effects of IL-13 are mediated largely by the downstream actions of TGF-β. b | Because fibroblasts express IL-13 receptors (IL-13Rs), IL-13 might also directly activate the collagen-producing machinery in fibroblasts-. c | IL-13 can also promote the alternative activation of macrophages and/or fibroblasts. By upregulating arginase activity in these cells, IL-13 increases l-ornithine, l-proline and polyamine concentrations, which promotes fibroblast proliferation, collagen production and ultimately, fibrosis. Interferon-γ (IFN-γ) produced by TH1 cells seems to antagonize all of these pathways. IFN-γ inhibits alternative macrophage activation, inducing nitric-oxide synthase 2 (NOS2) instead of arginase, and directly decreases collagen synthesis by fibroblasts. NOS2 activity promotes the production of l-hydroxyarginine, l-citrulline and nitric oxide. The intermediate by product l-hydroxyarginine also functions as a potent inhibitor of arginase activity, which can further antagonize the fibrotic pathway. OAT, ornithine amino transferase; ODC, ornithine decarboxylase.

Publication

FIBROTIC DISEASE AND THE TH1/TH2 PARADIGM. () Thomas A. Wynn. Nat Rev Immunol. ;4(8):583-594. Figure: F3. Homo sapiens

Disease mentions