Interleukin‐10 Response Abnormalities in Systemic Lupus Erythematosus

Abstract

It has been previously reported that the production of interleukin‐6 (IL‐6) is often enhanced in systemic lupus erythematosus (SLE). The authors examined the secretion of IL‐6, tumour necrosis factor‐α (TNF‐α), granulocyte–macrophage colony‐stimulating factor, IL‐1α and IL‐4 by B cells and monocytes from lupus patients and compared this to the production in normal controls and in rheumatoid arthritis patients. IL‐6 production was increased an average of 3.4‐fold compared to that in normal subjects and 8.4‐fold compared to rheumatoid arthritis patients. In SLE, a strongly positive correlation was found between the levels of IL‐6 and TNF‐α (R = 0.8987, P = 0.002). Since production of both IL‐6 and TNF‐α is regulated by IL‐10, the enhancement of the production of these cytokines could reflect a defect in either IL‐10 production or responsiveness. However, spontaneous production of IL‐10 was enhanced in cultures of B cells and monocytes from lupus patients, compared to normal controls, the levels being increased 3.1‐ to 6‐fold for monocytes and B cells, respectively. The finding of increased secretion of these cytokines implies an abnormality in IL‐10‐mediated suppression in SLE. To assess this possibility, the authors examined recombinant human IL‐10‐mediated suppression of IL‐6 production by monocytes and B cells from lupus patients, compared to normal controls, and found that whereas IL‐10 caused a concentration‐dependent suppression of IL‐6 production in normal B cells and monocytes, this suppression was deficient in B cells and monocytes from lupus patients. In SLE, it therefore appears that there may be an intrinsic defect in IL‐10‐induced suppression of cytokine synthesis. This could explain the increased levels of IL‐10 and IL‐6 found in this condition, and may also be responsible for the characteristic polyclonal B‐cell activation that is seen.

Sp1 binds to the G allele of the−1087 polymorphism in the IL-10 promoter and promotes IL-10 mRNA transcription and protein production

“…11 B-cells were found to produce high levels of IL-10 in several autoimmune diseases, for example Sjö gren's syndrome, rheumatoid arthritis and systemic lupus erythematousus. [12][13][14][15] The main source of B-cell-derived IL-10 is B-1a cells. 16 Larger relative proportions of B-1a cells and higher levels of IL-10 were found in the gingival lesions than in peripheral blood in subjects with chronic periodontitis.…”

The Sp1 transcription factor binds to the G-allele of the –1087 IL-10 gene polymorphism and enhances transcriptional activation

“…4 Following activation, B cells were found to produce high levels of IL-10 in several autoimmune diseases, for example, Sjö gren's syndrome, rheumatoid arthritis and systemic lupus erythematosus. [5][6][7][8] The main source of B-cell-derived IL-10 is autoreactive B (B-1a) cells. 9 Large numbers of B-1a cells were found in subjects with Sjö gren's syndrome or rheumatoid arthritis.…”

Novel Single Nucleotide Polymorphisms in the Distal IL-10 Promoter Affect IL-10 Production and Enhance the Risk of Systemic Lupus Erythematosus

“…The implication of a heritable genetic basis for IL-10 production is supported by the concordance of IL-10 production in monozygotic twins, which suggests that genetics could account for up to 75% of IL-10 production (10). Indeed, the high IL-10 production associated with autoimmune diseases including rheumatoid arthritis (RA) and SLE may be a genetic risk factor for disease susceptibility (2,8,(11)(12)(13)(14)(15)(16)(17)(18)(19).…”