IL-1.BETA. Genotype-Related Effect of Prednisolone on IL-1.BETA. Production in Human Peripheral Blood Mononuclear Cells under Acute Inflammation

Abstract

Glucocorticoids are potent anti-inflammatory and immunosuppressive drugs and consequently are widely used in the treatment of systemic inflammatory, allergic, and autoimmune diseases. The anti-inflammatory properties of glucocorticoids are mainly ascribed to their ability to suppress the synthesis of pro-inflammatory cytokines.1) But there is a certain percentage of patients, resistant to glucocorticoid-based anti-inflammatory therapy, who show high levels of local and/or systemic pro-inflammatory cytokines during glucocorticoid treatment. 2,3)IL-1b is considered to trigger a cascade of other pro-inflammatory cytokines and then maintain inflammation. [4][5][6] Therefore, the high inter-individual variation in IL-1b production may result in the different intensity of the inflammatory process among subjects, and possibly may lead to interindividual differences in the response to glucocorticoids. Recent advances in molecular genetics have suggested an association of IL-1b production intensity with genotype, especially with single nucleotide polymorphisms (SNPs) at positions Ϫ1470, Ϫ511, and Ϫ31 in the promoter region and at position 3954 in exon 5 of the IL-1b gene, but results have been inconsistent. There are two reports demonstrating an association of the TT Ϫ31 and CC Ϫ511 genotypes with increased IL-1b mRNA expression and protein release in Japanese 7) and Chinese populations, 8) and one report claiming an association of the TT Ϫ31 and CC Ϫ511 genotypes with less intensive IL-1b production in Caucasians. 9) Also, Pociot et al. 10)found an association between the C3954T polymorphism and IL-1b production, but in later studies by Hall et al. 9) and Kimura et al.,7) this association was not replicated. Finally, the GϪ1470C polymorphism, recently identified in a Chinese population, was also shown to influence IL-1b production as a component of a haplotype consisting ofThe present study was designed to examine the influence of IL-1b genotypes on the anti-inflammatory efficiency of glucocorticoids and its possible involvement in mechanisms of glucocorticoid-resistance. Specifically, the effect of prednisolone on lipopolysaccharide (LPS)-stimulated IL-1b mRNA expression and protein release, and its association with IL-1b genotypes, were analyzed. Earlier we showed that multidrug resistance transporter 1 (MDR1/P-glycoprotein), encoded by the ABCB1 gene, which possibly effluxes glucocorticoids out of target cells, was down-regulated in its expression under inflammatory conditions in relation to the ABCB1 C3435T genotype.11) The effect of the C3435T polymorphism on IL-1b production was also examined. MATERIALS AND METHODSSubjects Human PBMC were obtained from 19 healthy Japanese volunteers (12 males and 7 females), ranging in age from 23 to 43 years old. The subjects took no medications and had no noteworthy health problems. Informed consent was obtained from all subjects prior to their participation in the study. The protocol was approved by the Institutional Review Board of Kobe University Hospital, Kobe University, Ja...

IL-1β Is Overexpressed and Aberrantly Regulated in Corticosteroid Nonresponders with Autoimmune Inner Ear Disease

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Association of IL-1B genetic polymorphisms with an increased risk of opioid and alcohol dependence

“…IL-1B genotypes at positions -511, -31 and 3954 were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism assays as described earlier [43,44,49], except that different forward and reverse primers were used for the 3954 assay with the following sequences: forward, 5 0 -CTC AGG TGT CCT CCA AGA AAT CA-3 0 ; reverse, 5 0 -GCT TTT TTG CTG TGA GTC CCG-3 0 .…”