The type I interleukin-1 receptor acts in series with tumor necrosis factor (TNF) to induce arthritis in TNF-transgenic mice

Mehta VK, Hao W, Brooks-Worrell BM, Palmer JP. Low-dose interleukin 1 and tumor necrosis factor individually stimulate insulin release but in combination cause suppression. Eur J Endocrinol 1994;130:208–14. ISSN 0804–4643 The macrophage-derived cytokines interleukin 1 (IL-1) and tumor necrosis factor (TNF) have direct effects on pancreatic beta cells and have been hypothesized to play important roles in the autoimmune beta cell lesion of type I diabetes because of two major effects on beta cells: altered insulin secretion and beta cell cytotoxicity. High doses of IL-1 are cytotoxic to beta cells and strongly inhibit insulin release; high-dose IL-1 plus TNF acts synergistically to suppress further the insulin release. In contrast, we observed that the predominant effect of low-dose IL-1 and TNF when administered separately was the stimulation of insulin release. We therefore asked whether the combination of low-dose IL-1 plus TNF would act synergistically to stimulate or suppress insulin release. Studies were performed on cultured rat islets and both insulin release and cytotoxicity (51Cr release) were measured. After 2 days of culture, increasing doses of IL-1—25, 50, 75 and 100 ng/l—caused progressively increased cytotoxicity and impaired insulin release. In contrast, the lowest dose of IL-1 tested, 10 ng/l, increased insulin release but was still slightly cytotoxic. Tumor necrosis factor at doses of 10, 25, 62.5, 75 and 100 μg/l also was slightly cytotoxic but increased insulin release. The augmented insulin release declined progressively with increasing TNF dose. However the combination of insulin stimulatory doses of IL-1 (10 ng/l) and TNF (62.5 μg/l) suppressed insulin release. The effects of these two cytokines on insulin release demonstrated a similar pattern after 4 and 6 days of culture. Although both IL-1 and TNF are cytotoxic to cultured islets cells, the effects of these two cytokines on insulin release are markedly different: with IL-1 primarily suppressing and TNF increasing insulin release. In combination, IL-1 and TNF always inhibits insulin release. The lack of concordance between insulin release and cytotoxicity suggests that these cytokines may alter insulin release by at least two mechanisms, one dependent on and the other independent of cytotoxicity. Jerry P Palmer, Veterans Affairs Medical Center, Endocrinology (111) ZB-21. 1660 S Columbian Way, Seattle, WA 98108, USA

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Mumps Virus SH Protein Inhibits NF-κB Activation by Interacting with Tumor Necrosis Factor Receptor 1, Interleukin-1 Receptor 1, and Toll-Like Receptor 3 Complexes

Journal of Virology ◽

10.1128/jvi.01037-17 ◽

2017 ◽

Vol 91 (18) ◽

Cited By ~ 11

Author(s):

Stephanie Franz ◽

Paul Rennert ◽

Maria Woznik ◽

Josephine Grützke ◽

Amy Lüdde ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Interleukin 1 ◽

Tumor Necrosis Factor Receptor ◽

A549 Cells ◽

Mumps Virus ◽

Type I ◽

Tnf Α ◽

Infected Cells ◽

Necrosis Factor

ABSTRACT The mumps virus (MuV) small hydrophobic protein (SH) is a type I membrane protein expressed in infected cells. SH has been reported to interfere with innate immunity by inhibiting tumor necrosis factor alpha (TNF-α)-mediated apoptosis and NF-κB activation. To elucidate the underlying mechanism, we generated recombinant MuVs (rMuVs) expressing the SH protein with an N-terminal FLAG epitope or lacking SH expression due to the insertion of three stop codons into the SH gene. Using these viruses, we were able to show that SH reduces the phosphorylation of IKKβ, IκBα, and p65 as well as the translocation of p65 into the nucleus of infected A549 cells. Reporter gene assays revealed that SH interferes not only with TNF-α-mediated NF-κB activation but also with IL-1β- and poly(I·C)-mediated NF-κB activation, and that this inhibition occurs upstream of the NF-κB pathway components TRAF2, TRAF6, and TAK1. Since SH coimmunoprecipitated with tumor necrosis factor receptor 1 (TNFR1), RIP1, and IRAK1, we hypothesize that SH exerts its inhibitory function by interacting with TNFR1, interleukin-1 receptor type 1 (IL-1R1), and TLR3 complexes in the plasma membrane of infected cells. IMPORTANCE The MuV SH has been shown to impede TNF-α-mediated NF-κB activation and is therefore thought to contribute to viral immune evasion. However, the mechanisms by which SH mediates NF-κB inhibition remained largely unknown. In this study, we show that SH interacts with TNFR1, IL-1R1, and TLR3 complexes in infected cells. We thereby not only shed light on the mechanisms of SH-mediated NF-κB inhibition but also reveal that SH interferes with NF-κB activation induced by interleukin-1β (IL-1β) and double-stranded RNA.

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Interleukin-1 Contributes to Increased Concentrations of Soluble Tumor Necrosis Factor Receptor Type I in Sepsis

The Journal of Infectious Diseases ◽

10.1093/infdis/172.2.577 ◽

1995 ◽

Vol 172 (2) ◽

pp. 577-580 ◽

Cited By ~ 6

Author(s):

T. van der Poll ◽

E. Fischer ◽

S. M. Coyle ◽

K. J. Van Zee ◽

J. P. Pribble ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Interleukin 1 ◽

Tumor Necrosis Factor Receptor ◽

Receptor Type ◽

Type I ◽

Necrosis Factor

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Levels of Inhibitors of Tumor Necrosis Factor Alpha and Interleukin 1β in Urine and Sera of Patients with Urosepsis

Infection and Immunity ◽

10.1128/iai.66.8.3527-3534.1998 ◽

1998 ◽

Vol 66 (8) ◽

pp. 3527-3534 ◽

Cited By ~ 10

Author(s):

Dariusz P. Olszyna ◽

Jan M. Prins ◽

Barbara Buis ◽

Sander J. H. van Deventer ◽

Peter Speelman ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Interleukin 1 ◽

Interleukin 10 ◽

Cytokine Response ◽

Type I ◽

Necrosis Factor Alpha ◽

Tract Infections ◽

Antiinflammatory Cytokine ◽

Necrosis Factor

ABSTRACT The antiinflammatory cytokine response during urosepsis was determined by measurement of concentrations of soluble tumor necrosis factor receptor (sTNFR) types I and II, interleukin 1 receptor antagonist (IL-1ra), soluble IL-1 receptor type II (sIL-1RII), and interleukin 10 in sera and urine of 30 patients with culture-proven urinary tract infections before and 4, 24, 48, and 72 h after initiation of antibiotic therapy and in 20 healthy individuals. In serum, the levels of sTNFR types I and II, IL-1ra, and IL-10 were higher in patients than in controls. In urine, only sTNFR type I and II levels were elevated in patients. The ratios of concentrations of both types of sTNFR in urine to concentrations in serum were higher in patients than in controls. These findings indicate that during urosepsis, the antiinflammatory cytokine response is generated predominantly at the systemic level.

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