IL-7 inhibits fibroblast TGF-β production and signaling in pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with less than a 50% five-year survival (1, 2). While steroids and other immunosuppressive agents serve as the standard treatment for IPF, these agents have proved inadequate (3). In most instances immunosuppressive agents do little to affect the course of the disease and have serious adverse side effects. Thus, novel therapeutic strategies are clearly needed. Recent published findings suggest novel treatment paradigms based on a more complete understanding of the pathogenesis of pulmonary fibrosis (3, 4). IL-7 is a 25-kDa glycoprotein originally isolated from bone marrow stroma cells (5). IL-7 was originally defined as a pre-B lymphocyte growth factor and was subsequently found to augment the growth of T lymphocytes (6-8). We (9) and others (10-13) have documented that IL-7 can potently enhance T cell function and IFN-γ production. IL-7 synergizes with IL-12 in the induction of T cell proliferation, cytotoxicity, and IFN-γ release (11). In agreement with these findings are studies indicating that IL-7 plays a role in cell-mediated immune responses characteristic of type 1 cytokines (10). We have found that IL-7 downregulates macrophage (14), fibrosarcoma, and melanoma (15, 16) production of TGF-β. IL-7 has the capacity to downregulate the transcriptional rate of the TGF-β gene in murine macrophages in an IFN-γindependent manner (14). TGF-β is a critical fibrogenic factor in the development of pulmonary fibrosis. Based on the importance of TGF-β in the pathogenesis of pulmonary fibrosis, we speculated that the most effective therapies would be those that decrease both the production and the cellular effects of TGF-β. In the current study we investigate the role of IL-7 in TGF-β production and signaling and the potential for IL-7 as a new antifibrotic agent in the treatment of interstitial pulmonary fibrosis. Methods Cell culture. Pulmonary fibrosis fibroblasts (PFFs) were isolated from lung resection specimens obtained from patients with IPF. Normal fibroblasts (NFs) were isolated from patients with nonfibrotic diseases. U4A, U3A, and U4A/JAK1 cell lines were generously provided by George R. Stark (Cleveland Clinic Foundation, Cleveland, Ohio, USA). The cells were maintained in 5% CO 2 in air as monolayers at 37°C in 75-cm 2 tissue culture flasks containing 20 ml of DMEM supplemented with 10% FBS, 100 units/ml penicillin, 0.1 mg/ml streptomycin, and 2 mM glutamine (JRH Biosciences, Lenexa, Kansas, USA). Cytokines and antibodies. Human activated recombinant TGF-β1 (3.2 × 10 4 units/µg), recombinant human IL-7

New Insights into the Pathogenesis and Treatment of Idiopathic Pulmonary Fibrosis: A Potential Role for Stem Cells in the Lung Parenchyma and Implications for Therapy

“…In addition, it has been found that the expression of Smad 3 and 7 is down regulated during the process of lung fibrosis (207,208). Because TGFb is a key regulator of tissue remodeling, altered expression of its intracellular signaling molecule Smad 7 (a major inhibitory regulator in the Smad family) is likely to play an important role in the pathogenesis of PF (208).…”

“…Because TGFb is a key regulator of tissue remodeling, altered expression of its intracellular signaling molecule Smad 7 (a major inhibitory regulator in the Smad family) is likely to play an important role in the pathogenesis of PF (208). In addition, recent studies have found that over expression of both Smad 7 and IL-7 antagonize TGFb signaling and attenuate fibrosis in BIPF in mice (207,208).…”

IL-7 and IL-15: therapeutic cytokines for immunodeficiency

“…Transforming growth factor-b (TGF-b) can inhibit proliferation of pre-B cells induced by IL-7 and suppress the production of IL-7 by BM stromal cells [7]. Because IL-7 can inhibit TGF-b production by macrophages and fibroblasts, possibly through the upregulation of the TGF-b inhibitor Smad7 [8], both cytokines can regulate each other in a negative feedback loop.…”

Smad7 in TGF-β-mediated negative regulation of gut inflammation

“…Smad7 is induced in cell lines by the STAT1 (signal transducer and activator of T cells 1) pathway following activation with interferon-g (IFN-g) or interleukin-7 (IL-7), or by activated NF-kB following stimulation of cells with TNF-a [28][29][30]. TGF-b1 itself can also increase Smad7 [25].…”