A Role for IFN-αβ in Virus Infection-Induced Sensitization to Endotoxin

Abstract

Underlying viral infections can heighten sensitivity and worsen cytokine-mediated disease following secondary inflammatory challenges. Mechanisms for this are poorly understood. The impact of the innate response to lymphocytic choriomeningitis virus (LCMV) infection on sensitivity to endotoxin (LPS) was investigated. Compared with uninfected mice, infection with LCMV for 2-days-sensitized mice to LPS by ∼2-fold for lethality and by 2- to 6-fold for serum TNF-α levels. Priming for LPS-induced TNF-α was also seen with splenic and peritoneal leukocytes isolated from infected mice and challenged with LPS ex vivo. The effect on TNF-α production was present in the absence of IFN-γ, its major producers NK and T cells, and the major pathways for its induction through IL-12 and the signal transducer and activator of transcription 4 (STAT4), and therefore was IFN-γ independent. Early LCMV infection induces high concentrations of the type 1 IFNs, IFN-αβ. Administration of recombinant IFN-α alone heightened the TNF-α response to LPS. Innate IFN-αβ and IFN-γ responses to LCMV exist in a delicate balance. To reduce priming for LPS-induced TNF-α during LCMV, deficiencies in both the IFN-αβ and IFN-γ receptors or STAT1, a transcription factor downstream to both IFNs, were required. These data demonstrate that early viral infection can enhance sensitivity to bacterial products, and that this sensitization can occur in part as a result of endogenously expressed IFN-αβ. This work also raises issues about potential complications associated with IFN-αβ therapies.

Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

“…Indeed, virus-induced production of chemokines is known to be important for T-cell migration into peripheral tissues and efficient antigen clearance 15 , and chemokine production in pancreatic islets has been shown to have a role in T-cell infiltration into this organ 16 . Tolllike receptor (TLR) signaling following recognition of distinct pathogen patterns can also influence the production of proinflammatory cytokines and chemokines by DCs and macrophages [17][18][19][20][21] . Eleven different TLRs have been identified so far 22 , and these recognize molecular patterns such as RNA (receptors TLR3, TLR7 and TLR8) 23,24 , DNA (TLR9) 25 or l ipopolysaccharide (TLR4) 26 .…”

Coordinated and Distinct Roles for IFN-αβ, IL-12, and IL-15 Regulation of NK Cell Responses to Viral Infection

“…It was purified and had no detectable endotoxin, i.e., LPS, using standard assays. However, because previous work from our laboratory has demonstrated that sensitivity to endotoxin can be increased 10-to 100-fold during viral infections (37,38), and because treatment of both mutated and functional sIL-15R␣ had stimulatory effects on NK cells in C57BL/6 mice, experiments with this reagent were performed in the endotoxin-resistant C3H/ HeJ mice. Under these conditions, this very specific blocker of IL-15 functions inhibited the accumulation of NK cells.…”

Melphalan-Induced Expression of IFN-β in MOPC-315 Tumor-Bearing Mice and Its Importance for the Up-Regulation of TNF-α Expression

“…First, Schiavoni et al (19) have recently reported elevated expression of type I IFNs in the spleen of normal mice at 6 h after CY administration (the earliest time point studied), which was associated with subsequent elevation in biological activity of type I IFNs in the sera of the CY-treated mice. Second, type I IFNs were reported to favor the development of a type 1 cytokine response in nontumor systems (20 -23) and to prime mice for elevated production of TNF-␣ in response to LPS (24). As a representative of the type I IFNs, we decided to focus our attention on IFN-␤ and not IFN-␣ because there is a single IFN-␤, whereas there are multiple subtypes of IFN-␣ (25).…”