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Interferon-? and tumor necrosis factor-? act synergistically to up-regulate tissue factor in alveolar epithelial cells.

ABSTRACT: Fibrin deposition mediated through activation of tissue factor (TF) in the airspace is central to the pathogenesis of acute lung injury. Defining the mechanisms of TF regulation in the lung is critical to understanding pulmonary fibrin formation. Tumor necrosis factor-? (TNF-?) up-regulates TF in the injured lung, and there is emerging evidence that another cytokine, interferon-? (IFN-?), also modulates expression. The effects of TNF-? and IFN-? on regulation of TF were studied in alveolar epithelial A549 cells. In addition, potential mechanisms of modulation of TF expression by the 2 cytokines were analyzed with the hypothesis that IFN-? acts synergistically with TNF-? to up-regulate alveolar epithelial TF through modulation of TNF receptor (TNFR) expression. TNF-? but not IFN-? treatment increased TF mRNA, protein, and cell surface TF activity. The combination of IFN-? and TNF-? treatment augmented the effects of TNF-? on TF up-regulation and also increased release of procoagulant microparticles (MPs) from A549 cells. IFN-? modulated expression of both TNF-? receptors. Studies utilizing neutralizing antibodies against the two TNF receptors showed that the TF effects were mediated primarily through augmentation of TNFR1-dependent cellular responses. These findings have important implications for regulation of fibrin formation in the lung in the setting of acute inflammation.

SUBMITTER: Bastarache JA

PROVIDER: S-EPMC3652424 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Project description:Interferon (IFN) family cytokines stimulate genes (interferon-stimulated genes [ISGs]) that are integral to antiviral host defense. Type I IFNs act systemically, whereas type III IFNs act preferentially at epithelial barriers. Among barrier cells, intestinal epithelial cells (IECs) are particularly dependent on type III IFN for the control and clearance of virus infection, but the physiological basis of this selective IFN response is not well understood. Here, we confirm that type III IFN treatment elicits robust and uniform ISG expression in neonatal mouse IECs and inhibits the replication of IEC-tropic rotavirus. In contrast, type I IFN elicits a marginal ISG response in neonatal mouse IECs and does not inhibit rotavirus replication. In vitro treatment of IEC organoids with type III IFN results in ISG expression that mirrors the in vivo type III IFN response. However, IEC organoids have increased expression of the type I IFN receptor relative to neonate IECs, and the response of IEC organoids to type I IFN is strikingly increased in magnitude and scope relative to type III IFN. The expanded type I IFN-specific response includes proapoptotic genes and potentiates toxicity triggered by tumor necrosis factor alpha (TNF-α). The ISGs stimulated in common by type I and III IFNs have strong interferon-stimulated response element (ISRE) promoter motifs, whereas the expanded set of type I IFN-specific ISGs, including proapoptotic genes, have weak ISRE motifs. Thus, the preferential responsiveness of IECs to type III IFN in vivo enables selective ISG expression during infection that confers antiviral protection but minimizes disruption of intestinal homeostasis.IMPORTANCE Enteric viral infections are a major cause of gastroenteritis worldwide and have the potential to trigger or exacerbate intestinal inflammatory diseases. Prior studies have identified specialized innate immune responses that are active in the intestinal epithelium following viral infection, but our understanding of the benefits of such an epithelium-specific response is incomplete. Here, we show that the intestinal epithelial antiviral response is programmed to enable protection while minimizing epithelial cytotoxicity that can often accompany an inflammatory response. Our findings offer new insight into the benefits of a tailored innate immune response at the intestinal barrier and suggest how dysregulation of this response could promote inflammatory disease.

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Interferon-? and tumor necrosis factor-? act synergistically to up-regulate tissue factor in alveolar epithelial cells.

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