Interindividual variations in constitutive interleukin-10 messenger RNA and protein levels and their association with genetic polymorphisms1

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Abstract
Genetic variations in the interleukin (IL)-10 gene promoter have been associated with levels of induced production of IL-10, disease susceptibility, and allograft rejection. Small amounts of this cytokine are constitutively produced and are important in maintaining the physiologic function of the cytokine network. In this study, we evaluated the distribution of IL-10 basal levels and its genetic regulation in a healthy Spanish population. Polymorphisms at the -1,082, -819, and -512 positions of the IL-10 promoter were analyzed by polymerase chain reaction amplification and hybridization with fluorescent-labeled allele-specific probes in 183 Spanish people. Levels of IL-10 messenger (m)RNA were tested by real-time reverse transcription-polymerase chain reaction in 123 healthy donors. Serum concentrations of IL-10 were measured by a highly sensitive ELISA, whereas protein amounts in lipopolysaccharide culture supernatants were quantified by an in-house ELISA. The frequency of IL-10 promoter alleles and haplotypes in our population showed remarkable differences from other Caucasian populations. Large interindividual variations were found in mRNA and protein constitutive levels of IL-10, which allowed its classification in low and intermediate/high producers. We found statistical differences in mRNA concentration between the polymorphic variant GCC/GCC and the low producer genotypes. The G allele at position -1082 was the most important genetic factor in the regulation of constitutive IL-10 mRNA levels. Similarly, we also found an association of this polymorphic position with serum concentration greater than 2 pg/mL. Constitutive levels of IL-10 (mRNA and serum protein) displayed remarkable interindividual variations, which are genetically controlled by polymorphic variants at the cytokine gene promoter.