Complex effects of IL1A polymorphism and calpain inhibitors on interleukin 1α (IL-1α) mRNA levels and secretion of IL-1α protein

S. Lee, Suzanna Lindsey-Temple, S. Roberts, Patricia Price

    Research output: Contribution to journalArticle

    8 Citations (Scopus)

    Abstract

    Alleles of IL1A-889(C > T) and IL1A+4845(G > T) are in linkage disequilibrium. Interleukin 1 alpha (IL-1 alpha) 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-1 alpha protein than cells from IL1A(1,1) donors, while release from IL1A(2,2) cells was variable. Genotype did not affect levels of IL-1 alpha mRNA, so differential cleavage of the precursor is a feasible mechanism. However, genotype also had no effect on inhibition of IL-1 alpha release by pretreatment with calpain inhibitors, and calpain inhibitors reduced IL-1 alpha and tumor necrosis factor alpha mRNA levels. Hence, calpain inhibitors probably affect inhibition of signal transduction pathway rather than cleavage of IL-1 alpha protein. As ratios of mu-calpain/calpastatin were lowest in heterozygous donors, genetically determined IL-1 alpha levels may modulate transcription of calpain and calpastatin. This could reduce the impact of IL1A genotype on IL-1 alpha secretion and amplify individual variation in levels generated in culture.
    Original languageEnglish
    Pages (from-to)67-71
    JournalTissue Antigens
    Volume72
    DOIs
    Publication statusPublished - 2008

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