Interferon-γ and tumor necrosis factor-α 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-α (TNF-α) upregulates TF in the injured lung, and there is emerging evidence that another cytokine, interferon-γ (IFN-γ) 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 two cytokines were analyzed with the hypothesis that IFN-γ acts synergistically with TNF-α to upregulate alveolar epithelial TF through modulation of TNFR expression. TNF-α but not IFN-γ treatment increased TF mRNA, protein and cell surface TF activity. The combination of IFN-γ and TNF-α treatment augmented the effects of TNF-α on TF upregulation and also increased release of procoagulant microparticles (MPs) from A549 cells. IFN-γ modulated expression of both TNF-α receptors, studies utilizing neutralizing antibodies against the two TNF receptors showed the TF effects were mediated primarily through augmenting TNFR1-dependent cellular responses. These findings have important implications for regulation of fibrin formation in the lung in the setting of acute inflammation.

Vitamin D modulates tissue factor and protease‐activated receptor 2 expression in vascular smooth muscle cells

“…Previous studies have demonstrated that TNF‐α increased TF expression and cell surface TF activity of alveolar epithelial A549 cells (32). Moreover, increasing concentrations of TNF‐α resulted in a graded increase of TF expression in cultured VSMCs (33).…”

Analysis of cytotoxicity induced by proinflammatory cytokines in the human alveolar epithelial cell line A549

“…In this study, we evaluated the cytotoxicity induced by a mixture of proinflammatory cytokines (IL-1β/ TNF-α/IFN-γ), which have been suggested to play major roles in sepsis or ALI (5,(8)(9)(10)(11)(12)(13), in the human alveolar epithelial cell line A549. Then, to clarify the cytotoxic signaling pathways responsible for alveolar epithelial cell injury, various agents with antiinflammatory or antioxidative properties were screened for cytoprotective effects in an in vitro acute lung injury model (9,(14)(15)(16)(17).…”

“…Then, to clarify the cytotoxic signaling pathways responsible for alveolar epithelial cell injury, various agents with antiinflammatory or antioxidative properties were screened for cytoprotective effects in an in vitro acute lung injury model (9,(14)(15)(16)(17).…”

Microparticles and acute lung injury

“…Patients who died had a trend toward a higher MP concentration in lung edema fluid compared with those who survived (P ϭ 0.073), attesting to a detrimental effect of MPs in ALI/ARDS. Similar MPs could be generated in vitro by stimulation of cultured alveolar epithelial cells with a mix of the proinflammatory mediators TNF-␣, IL-1␤, and interferon-␥ (16,17). Whereas both ARDS and non-ARDS controls in Bastarache's study were severely sick, BALF analyses from healthy pigs with volume-controlled ventilation set to maintain normocapnia (37.5-41 mmHg Pa CO 2 ) with 5 cmH 2 O positive endexpiratory pressure revealed PMPs that were positive for fibrinogen, vWF, and P-selectin (124).…”