Soluble murine IL-1 receptor type I induces release of constitutive IL-1 alpha.
IL-1 alpha and IL-1 beta are proinflammatory cytokines involved in the pathogenesis of many infectious and noninfectious inflammatory diseases. To reduce IL-1 toxicity, extracellular domains of the soluble (s) IL-1R are shed from cell membranes and prevent triggering of cell-bound receptors. We investigated to what extent murine sIL-1RI can neutralize the IL-1 produced by LPS-stimulated macrophages. When mouse peritoneal macrophages were incubated with LPS, addition of sIL-1RI significantly inhibited the bioactivity of IL-1. Stimulation of cells with sIL-1RI alone induced no bioactive IL-1. When immunoreactive cytokine concentrations were measured with specific radioimmunoassays, sIL-1RI alone appeared to induce a significant release of IL-1 alpha in a concentration-dependent manner. This effect was independent of new protein synthesis. The production of IL-1 beta or TNF-alpha was not influenced by sIL-1RI. There was no interference of sIL-1RI with the IL-1 alpha radioimmunoassay. In mice, an i.v. injection of sIL-RI alone induced a rapid release of IL-1 alpha, but not of TNF-alpha or IL-1 beta. Treatment of mice with sIL-1RI improved the survival during a lethal infection with Candida albicans. In conclusion, sIL-1RI induces a rapid release of IL-1 alpha from cells, as well as into the systemic circulation. Although this IL-1 alpha may be inactivated in circulation by the same sIL-1RI, this phenomenon probably has immunostimulatory effects at local levels where the sIL-1RI-induced IL-1 alpha acts in a paracrine or autocrine manner.
Netea
M G
MG
Division of General Internal Medicine, Department of Medicine and Nuclear Medicine, University Hospital Nijmegen, The Netherlands.
Kullberg
B J
BJ
Boerman
O C
OC
Verschueren
I
I
Dinarello
C A
CA
Van der Meer
J W
JW
D000818:Animals; D002177:Candidiasis / Q000276:immunology / Q000628:therapy; D002474:Cell-Free System / Q000276:immunology / Q000378:metabolism; D002850:Chromatography, Gel; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D009503:Neutropenia / Q000276:immunology / Q000628:therapy; D011485:Protein Binding / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D053573:Receptors, Interleukin-1 Type I; D012995:Solubility
D007375:Interleukin-1; D008070:Lipopolysaccharides; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I