Complex effects of IL1A polymorphism and calpain inhibitors on interleukin 1 alpha (IL-1 alpha) mRNA levels and secretion of IL-1 alpha protein.
Alleles of IL1A-889(C>T) and IL1A+4845(G>T) are in linkage disequilibrium. Interleukin 1alpha (IL-1alpha) is produced as a precursor protein and cleaved at positions 117-118 by calpain, generating a mature protein for export. IL1A+4845 affects amino acids expressed at position 114 and hence may modulate calpain-mediated cleavage. We sought evidence for this mechanism in intact cells. Blood leukocytes from heterozygous donors released more IL-1alpha protein than cells from IL1A(1,1) donors, while release from IL1A(2,2) cells was variable. Genotype did not affect levels of IL-1alpha mRNA, so differential cleavage of the precursor is a feasible mechanism. However, genotype also had no effect on inhibition of IL-1alpha release by pretreatment with calpain inhibitors, and calpain inhibitors reduced IL-1alpha and tumor necrosis factor alpha mRNA levels. Hence, calpain inhibitors probably affect inhibition of signal transduction pathway rather than cleavage of IL-1alpha protein. As ratios of mu-calpain/calpastatin were lowest in heterozygous donors, genetically determined IL-1alpha levels may modulate transcription of calpain and calpastatin. This could reduce the impact of IL1A genotype on IL-1alpha secretion and amplify individual variation in levels generated in culture.
Lee
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Department of Clinical Immunology and Immunogenetics, Royal Perth Hospital, University of Western Australia, Perth, Australia. lees06@cyllene.uwa.edu.au
Temple
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Roberts
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Price
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D000179:Acrylates / Q000494:pharmacology; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000502:physiology; D002478:Cells, Cultured; D004151:Dipeptides / Q000502:physiology; D006023:Glycoproteins / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D053582:Interleukin-1alpha / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D007976:Leupeptins / Q000502:physiology; D011110:Polymorphism, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D000179:Acrylates; D004151:Dipeptides; D006023:Glycoproteins; D053582:Interleukin-1alpha; D007976:Leupeptins; C100442:PD 150606; D012333:RNA, Messenger; C039304:calpain inhibitors; C063261:acetylleucyl-leucyl-norleucinal; C071482:calpeptin; D002154:Calpain