Interleukin-9 Reduces Lung Fibrosis and Type 2 Immune Polarization Induced by Silica Particles in a Murine Model

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207

189

Increased lung IL-4 expression in pulmonary fibrosis suggests a potential pathogenetic role for this cytokine. To dissect this role, bleomycin-induced pulmonary inflammation and fibrosis were analyzed and compared in wild type (IL-4+/+) vs IL-4-deficient (IL-4−/−) mice. Lethal pulmonary injury after bleomycin treatment was higher in IL-4−/− vs IL-4+/+ mice. By administration of anti-CD3 Abs, we demonstrated that this early response was linked to the marked T lymphocyte lung infiltration and to the overproduction of the proinflammatory mediators such as TNF-α, IFN-γ, and NO in IL-4−/− mice. In contrast to this early anti-inflammatory/immunosuppressive role, during later stages of fibrosis, IL-4 played a profibrotic role since IL-4−/− mice developed significantly less pulmonary fibrosis relative to IL-4+/+ mice. However, IL-4 failed to directly stimulate proliferation, α-smooth muscle actin, and type I collagen expression in lung fibroblasts isolated from the wild-type mice. Upon appropriate stimulation with other known fibrogenic cytokines, fibroblasts from IL-4−/− mice were relatively deficient in the studied parameters in comparison to fibroblasts isolated from IL-4+/+ mice. Taken together, these data suggest dual effects of IL-4 in this model of lung fibrosis: 1) limiting early recruitment of T lymphocytes, and 2) stimulation of fibrosis chronically.

mentioning

confidence: 63%

Dual Roles of IL-4 in Lung Injury and Fibrosis

Huaux

Liu

McGarry

et al. 2003

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207

189

“…This protective effect, also observed with IL-4, was associated with a strong reduction of serum levels of TNF-␣, IL-12/p40, and IFN-␥ induced by the bacteria or LPS injection, and with a dramatic increase of IL-10. Secondly, in a silica-induced lung fibrosis model, IL-9 had a beneficial antifibrotic effect associated with an inhibition of the silica-induced up-regulation of IL-4 expression (14). Interestingly, in a rat model of lung fibrosis induced by irradiation, IL-4 has been shown to be mostly produced by alveolar macrophages (15).…”

Section: Il-9 Inhibits Oxidative Burst and Tnf-␣ Release In Lipopolysmentioning

confidence: 98%

IL-9 Inhibits Oxidative Burst and TNF-α Release in Lipopolysaccharide-Stimulated Human Monocytes Through TGF-β

Pilette¹,

Ouadrhiri²,

Snick

et al. 2002

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IL-9 is a Th2 cytokine that exerts pleiotropic activities on T cells, B cells, mast cells, hematopoietic progenitors, and lung epithelial cells, but no effect of this cytokine has been reported so far on mononuclear phagocytes. Human blood monocytes preincubated with IL-9 for 24 h before LPS or PMA stimulation exhibited a decreased oxidative burst, even in the presence of IFN-γ. The inhibitory effect of IL-9 was specifically abolished by anti-hIL-9R mAb, and the presence of IL-9 receptors was demonstrated on human blood monocytes by FACS. IL-9 also down-regulated TNF-α and IL-10 release by LPS-stimulated monocytes. In addition, IL-9 strongly up-regulated the production of TGF-β1 by LPS-stimulated monocytes. The suppressive effect of IL-9 on the respiratory burst and TNF-α production in LPS-stimulated monocytes was significantly inhibited by anti-TGF-β1, but not by anti-IL-10Rβ mAb. Furthermore, IL-9 inhibited LPS-induced activation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases in monocytes through a TGF-β-mediated induction of protein phosphatase activity. In contrast, IL-4, which exerts a similar inhibitory effect on the oxidative burst and TNF-α release by monocytes, acts primarily through a down-regulation of LPS receptors. Thus, IL-9 deactivates LPS-stimulated blood mononuclear phagocytes, and the mechanism of inhibition involves the potentiation of TGF-β1 production and extracellular signal-regulated kinase inhibition. These findings highlight a new target cell for IL-9 and may account for the beneficial activity of IL-9 in animal models of exaggerated inflammatory response.

“…ODN contained Ͻ0.1 units of endotoxin/mg, as assessed by a Limulus amebocyte cell lysate assay. Silica particles were obtained from U.S. Silica and were sterilized at 200°C for 2 h to inactivate any contaminating endotoxin (25).…”

Section: Odns and Reagentsmentioning

confidence: 99%

Suppressive Oligodeoxynucleotides Inhibit Silica-Induced Pulmonary Inflammation

Sato¹,

Shimosato²,

Alvord

et al. 2008

Inhalation of silica-containing dust particles induces silicosis, an inflammatory disease of the lungs characterized by the infiltration of macrophages and neutrophils into the lungs and the production of proinflammatory cytokines, chemokines, and reactive oxygen species (ROS). Synthetic oligodeoxynucleotides (ODN) expressing “immunosuppressive motifs” were recently shown to block pathologic inflammatory reactions in murine models of autoimmune disease. Based on those findings, the potential of suppressive ODN to prevent acute murine silicosis was examined. In vitro studies indicate that suppressive ODN blunt silica-induced macrophage toxicity. This effect was associated with a reduction in ROS production and p47phox expression (a subunit of NADPH oxidase key to ROS generation). In vivo studies show that pretreatment with suppressive (but not control) ODN reduces silica-dependent pulmonary inflammation, as manifest by fewer infiltrating cells, less cytokine/chemokine production, and lower levels of ROS (p < 0.01 for all parameters). Treatment with suppressive ODN also reduced disease severity and improved the survival (p < 0.05) of mice exposed to silica.