Endogenous interferon specifically regulates Newcastle disease virus-induced cytokine gene expression in mouse macrophages

Abstract

In macrophages from inbred mice, the magnitude of the interferon (IFN) response to Newcastle disease virus (NDV) infection is under genetic control of the If-1 locus, which carries the allele for either high (h) or low (l) IFN production. Here, we report that the activity of genes within the If-1 locus is influenced by macrophage-derived endogenous IFN. In addition to various other biological effects, we observed that endogenous IFN specifically downregulated NDV-induced IFN and interleukin 6 production. Preculture of bone marrow-derived macrophages (BMM) from BALB/c (If-1l) mice in macrophage colony-stimulating factor plus anti-IFN-beta provoked a 30- to 50-fold increase in NDV-induced cytokine production compared with induced control cultures in macrophage colony-stimulating factor alone, whereas only a 4- to 6-fold increase was observed in anti-IFN-beta-treated BMM from C57BL/6 (If-1h) mice. This resulted in nearly complete abrogation of the genetically determined difference in the response to NDV. The increase was specific for NDV and was marked by strong additional activation of IFN-alpha genes. Studies using BMM from B6.C-H28c If-1l congenic mice gave results identical to those obtained with BALB/c BMM. Addition of 20 IU of recombinant IFN-alpha 4 to anti IFN-beta-treated macrophages from B6.C-H28c mice 20 h prior to NDV infection strongly downregulated the IFN-alpha, IFN-beta, and interleukin 6 responses. The genetic difference between macrophages from If-1h and If-1l mice was thus reestablished, since the same treatment caused only weak reduction of NDV-induced cytokine gene expression in BMM from C57BL/6 mice. These data suggest that the If-1h and If-1l alleles harbor IFN-inducible genes that, following activation, specifically suppress subsequent cytokine gene expression in response to NDV.

Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro

“…Here, the impact of MEDI5395 infection on human immune-cell populations was examined. It has been demonstrated that NDV induces activation of immune-cell populations, including human PBMCs [18], NK cells [19,20], and mouse macrophages [21][22][23][24]. These findings are extended here with a comprehensive analysis of human PBMC populations acting as surrogates for subsets of immune cells present within the TME and the peripheral circulation.…”

Newcastle disease virus infection in chicken embryonic fibroblasts but not duck embryonic fibroblasts is associated with elevated host innate immune response

“…Studies have demonstrated that NDV infection in immune cells—for instance, peripheral blood mononuclear cells and macrophages—results in extremely robust proinflammatory and antiviral cytokine induction both in vivo and in vitro [ 14 , 20 , 28 , 29 ]. The expression of cytokines such as LITAF , IL-1beta , IL-8 and IL-6 in splenic leukocytes, macrophages and lymphoid tissues in chickens, ducks, geese and pigeons immediately are distinct in response to NDV infection [ 19 – 21 , 30 ].…”

Analysis of the transcriptional networks underpinning the activation of murine macrophages by inflammatory mediators

“…The T lymphocytes of BALB/c mice generate more IL-4 and Th2 cytokines, and these stimulate macrophage arginine metabolism by inducing arginase [ 26 ]. Another key difference between the strains is the autocrine IFN signaling in C57BL/6 mice; C57BL/6 macrophages display IFN-dependent, differential resistance to Newcastle disease virus [ 27 ] and respond to LPS as if IFN-primed [ 23 ]. Strain-specific methylation patterns have been shown to contribute to differences in gene expression between the two strains, including the Gbp1 gene [ 28 ], and their macrophages differ in response to Yersinia enterocolitica infection [ 29 ] and Leishmania major infection [ 30 ].…”