IFN-γ-Induced TNF-α Expression Is Regulated by Interferon Regulatory Factors 1 and 8 in Mouse Macrophages

Lung surfactant protein A (SP-A) plays an important function in modulating inflammation in the lung. However, the exact role of SP-A and the mechanism by which SP-A affects IFN-γ–induced activation of alveolar macrophages (aMϕs) remains unknown. To address these questions, we studied the effect of human SP-A on rat and human aMϕs stimulated with IFN-γ, LPS, and combinations thereof and measured the induction of proinflammatory mediators as well as SP-A’s ability to bind to IFN-γ or IFN-γR1. We found that SP-A inhibited (IFN-γ + LPS)–induced TNF-α, iNOS, and CXCL10 production by rat aMϕs. When rat macrophages were stimulated with LPS and IFN-γ separately, SP-A inhibited both LPS-induced signaling and IFN-γ–elicited STAT1 phosphorylation. SP-A also decreased TNF-α and CXCL10 secretion by ex vivo–cultured human aMϕs and M-CSF–derived macrophages stimulated by either LPS or IFN-γ or both. Hence, SP-A inhibited upregulation of IFN-γ–inducible genes (CXCL10, RARRES3, and ETV7) as well as STAT1 phosphorylation in human M-CSF–derived macrophages. In addition, we found that SP-A bound to human IFN-γ (KD = 11 ± 0.5 nM) in a Ca2+-dependent manner and prevented IFN-γ interaction with IFN-γR1 on human aMϕs. We conclude that SP-A inhibition of (IFN-γ + LPS) stimulation is due to SP-A attenuation of both inflammatory agents and that the binding of SP-A to IFN-γ abrogates IFN-γ effects on human macrophages, suppressing their classical activation and subsequent inflammatory response.

Section: Sp-a Inhibits Lps and Ifn-g Effects On Rat Amfscontrasting

confidence: 99%

Surfactant Protein A Prevents IFN-γ/IFN-γ Receptor Interaction and Attenuates Classical Activation of Human Alveolar Macrophages

Minutti

García-Fojeda

Sáenz

et al. 2016

“…This suggests that TNF-␣ up-regulates both mTGF-␤1 and endogenous TNF-␣ expression in this cell line and that TNF-␣ may induce mTGF-␤1. It has been reported that IFN-␥ induces TNF-␣-regulated signaling by inducing TNF-␣ expression in mouse macrophages (23,24). However, in our model, IFN-␥ alone is not sufficient to induce endogenous TNF-␣ expression.…”

Section: Tnf-␣ Is Also An Inducer Of Mtgf-␤1contrasting

confidence: 65%

Presence of Membrane-Bound TGF-β1 and Its Regulation by IL-2-Activated Immune Cell-Derived IFN-γ in Head and Neck Squamous Cell Carcinoma Cell Lines

Ahn

Lee²,

Sung³

et al. 2009

The presence of membrane-bound TGF-β1 (mTGF-β1) has been recently observed in regulatory T cells, but only a few studies have reported the same phenomenon in cancer cells. In this study, we investigate the regulation of mTGF-β1 expression in five head and neck squamous cell carcinoma cell lines using FACS analysis. Through blocking Ab and exogenous cytokine treatment experiments, we found that expression of mTGF-β1 is significantly induced by the activated immune cell-derived factor IFN-γ. In addition, IFN-γ and TNF-α are shown to have a synergistic effect on mTGF-β1 expression. Moreover, we found that exogenous TNF-α induces endogenous TNF-α mRNA expression in an autocrine loop. In contrast to previous reports, we confirm that, in this model, mTGF-β1 is neither a rebound form of once-secreted TGF-β1 nor an activated form of its precursor membrane latency-associated peptide. Inhibitors of transcription (actinomycin D), translation (cycloheximide), or membrane translocation (brefeldin A) effectively block the induction of mTGF-β1, which suggests that induction of mTGF-β1 by IFN-γ and/or TNF-α occurs through de novo synthesis. These findings suggest that some cancer cells can detect immune activating cytokines, such as IFN-γ and TNF-α, and actively block antitumor immunity by induction of mTGF-β1.

“…Macrophages and T cells are considered to be the main source of TNF-a. Production of TNF-a in macrophages is regulated by TLR via activation of NF-kB and by IFN-g via activation of IFN regulatory factors during infection (23,24). The production of TNF-a in Th1 cells is transcriptionally regulated by T-bet (25,26).…”

Section: Discussionmentioning

confidence: 99%

Role of Th1/Th17 Balance Regulated by T-bet in a Mouse Model of Mycobacterium avium Complex Disease

Matsuyama

Ishii

Yageta

et al. 2014

Th1 immune responses are thought to be important in protection against intracellular pathogens. T-bet is a critical regulator for Th1 cell differentiation and Th1 cytokine production. The aim of this study was to determine the role of T-bet in host defense against Mycobacterium avium complex (MAC) infection. Wild-type mice, T-bet–deficient mice, and T-bet–overexpressing mice were infected with MAC via intratracheal inoculation. Macrophages and dendritic cells obtained from these mice were incubated with MAC. T-bet–deficient mice were highly susceptible to MAC, compared with wild-type mice and T-bet–overexpressing mice. Neutrophilic pulmonary inflammation was also enhanced in T-bet–deficient mice, but attenuated in T-bet–overexpressing mice, following MAC infection. Cytokine expression shifted toward Th1 in the lung and spleen of T-bet–overexpressing mice, but toward Th17 in T-bet–deficient mice. IFN-γ supplementation to T-bet–deficient mice reduced systemic MAC growth but did not reduce pulmonary inflammation. In contrast, neutralization of IL-17 in T-bet–deficient mice reduced pulmonary inflammation but did not affect mycobacterial growth in any organs tested. T-bet–deficient T cells tended to differentiate toward Th17 cells in vitro following exposure to MAC. Treatment with NO donor suppressed MAC-induced Th17 cell differentiation of T-bet–deficient T cells. This study identified that the fine balance between Th1 and Th17 responses is essential in defining the outcome of MAC disease. T-bet functions as a regulator for Th1/Th17 balance and is a critical determinant for host resistance to MAC infection by controlling cytokine and NO levels.