Evidence that high mannose glycopeptides are able to functionally interact with recombinant tumor necrosis factor and recombinant interleukin 1.
Both recombinant tumor necrosis factor (rTNF) and recombinant interleukin 1 (rIL-1) are able to mediate vascular collapse and death in a previously described murine model, using galactosamine to enhance the toxicity of these cytokines. Unexpectedly, both acid-treated tumor necrosis factor (TNF) and a site-specifically mutagenized form of interleukin 1 (IL-1) (His-30----Arg-30), which fails to bind to the IL-1 receptor, retain full in vivo toxicity in this model of TNF- and IL-1-mediated shock. Previous studies have shown that rTNF and rIL-1 exhibit two functionally distinct binding regions. Both cytokines bind to their respective cell surface receptors and they also express lectin like binding specificity (Muchmore and Decker, J. Biol. Chem., 261: 13404-13407, 1986; Muchmore and Decker, J. Immunol., 138: 2541-2546, 1987) for defined oligosaccharides. The specificity of these two types of interactions is quite different. Cell surface receptors for IL-1 and TNF demonstrate essentially no cross-reactivity, whereas, in the case of carbohydrate binding, competition studies reveal an almost identical carbohydrate specificity for the structure Man5(6)GlcNAc2-Asn. Man5(6)GlcNAc2-Asn binding is either unaffected or actually enhanced by either acid treatment of rTNF or mutation at His-30 for rIL-1. Both deoxymannojirimycin and swainsonine, inhibitors of glycoprotein processing, raise intracellular levels of Man5-9GlcNAc2 and enhance the in vitro biological activity of both rTNF and rIL-1. Conversely, castanosperimine, a glucosidase I inhibitor which blocks the synthesis of mature high mannose structures, inhibits the biological activity of IL-1. These observations support the hypothesis that some effects of IL-1 and TNF may involve interaction with high mannose-substituted glycoproteins.
Metabolism Branch, National Cancer Institute, NIH, Bethesda, Maryland 20205.
A
A
Muchmore
J
J
Decker
A
A
Shaw
P
P
Wingfield
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D004347:Drug Interactions; D005688:Galactosamine / Q000008:administration & dosage / Q000633:toxicity; D006020:Glycopeptides / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000378:metabolism* / Q000633:toxicity*; D008358:Mannose / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011292:Premedication; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity
D006020:Glycopeptides; D007375:Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D008358:Mannose