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Table 1 Cytokines involved in the regulation of pulmonary fibrosis

From: Molecular and cellular mechanisms of pulmonary fibrosis

Mediators Effects Relevant to Pulmonary Fibrosis References
Growth Factors
Transforming growth factor-β (TGF-β) The major profibrotic growth factor. In vitro, stimulates fibroblast ECM production, myofibroblast differentiation, resistance to apoptosis, and production of ROS. Induces apoptosis in epithelial cells, and promotes epithelial-mesenchymal transdifferentiation (EMT). Upregulated in animal models of fibrosis, and overexpression in vivo induces severe fibrosis. [12, 2736]
Connective tissue growth factor (CTGF, CCN2) Stimulates fibroblast proliferation and ECM production in vitro. Upregulated in the bleomycin model, and overexpression in vivo induces mild fibrosis. Functions in combination with TGF-β. [3744]
Platelet-derived growth factor (PDGF) Stimulates fibroblast proliferation and chemotaxis in vitro. Upregulated in animal models of fibrosis, and inhibition reduces fibrosis. Upregulated in human fibrotic diseases, but inhibition did not improve survival in patients with IPF. [38, 4454]
Insulin-like growth factor (IGF) Stimulates fibroblast ECM production in vitro. Upregulated in the bleomycin model, but overexpression in vivo did not induce fibrosis. Stimulates proliferation of epithelial cells. [44, 5559]
Interleukin-4 (IL-4) Th-2 cytokines which stimulate fibroblast proliferation and ECM production in vitro. Upregulated in the bleomycin model, and overexpression in vivo induces fibrosis. Induce alternative activation of macrophages. [24, 25, 6068]
Interleukin-13 (IL-13)   
Interferon-γ (IFN-γ) Pro-inflammatory Th-1 cytokine which inhibits fibroblast proliferation and ECM production in vitro, and enhances fibroblast apoptosis. In vivo, reduces fibrosis in the bleomycin model, but administration in patients with IPF did not improve survival. [6977]
Interleukin-1β (IL-1β) Pro-inflammatory cytokines which in vitro stimulate fibroblast proliferation and chemotaxis, but inhibit collagen production. Upregulated in the bleomycin model, and overexpression in vivo induces inflammation and fibrosis, with fibrosis likely mediated by TGF-β. Inhibition of TNF-α in patients with IPF did not improve outcomes. [44, 7888]
Tumor necrosis factor-α (TNF-α)   
Interleukin-17 (IL-17) Pro-inflammatory cytokine which is upregulated in the bleomycin model. Exogenous administration in vivo induced fibrosis, which was reduced by blockade of TGF-β. Upregulated in patients with IPF. [25, 89, 90]
Oncostatin M (OSM) In fibroblasts, stimulates proliferation and ECM production in vitro, and inhibits apoptosis. Overexpression and exogenous administration in vivo induces inflammation and fibrosis, and fibrosis occurred independently of TGF-β. [9196]
Interleukin-10 (IL-10) Anti-inflammatory cytokine which inhibits fibroblast ECM production in vitro, and upregulation or overexpression in the bleomycin model reduced fibrosis. In vivo overexpression alone, however, induced fibrosis, likely mediated by CCL2. Induces alternative activation of macrophages. [68, 97100]
Chemokines
CCL2 (MCP-1) Pro-inflammatory CC chemokine which stimulates fibroblast ECM production and resistance to apoptosis in vitro. Upregulated in animal models of fibrosis, and in vivo loss of function (chemokine or receptor) reduces fibrosis. Recruits bone-marrow derived fibrocytes to the lung. [98, 101108]
CCL18 (PARC) Pro-inflammatory CC chemokine which mildly stimulates fibroblast ECM production in vitro. Overexpression in vivo induces fibrosis, however, overexpression combined with bleomycin reduced fibrosis. Serum concentrations inversely correlated with outcomes in patients with IPF and SSc. [109115]
CCL3 (MIP-1α) Pro-inflammatory CC chemokine which is upregulated in animal models of fibrosis, and in vivo loss of function (chemokine or receptor) reduces fibrosis. Recruits bone-marrow derived fibrocytes to the lung. [116119]
CXCL12 CXC chemokine which is upregulated in the bleomycin model, and is the major chemokines responsible for recruiting bone-marrow derived fibrocytes to the lung. Upregulated in BAL and serum in patients with IPF, and inversely correlated with physiologic parameters. [120122]