Corticosteroid effects on IL-10 and IL-1β in U937-derived macrophages: A model for Kawasaki disease-associated inflammation.

Abstract

Background: Kawasaki disease (KD) is a pediatric vasculitis that has a predilection for coronary artery involvement. Activated macrophages play an important role in the destruction of the coronary arteries in KD. Although intravenous immunoglobulin (IVIG) is standard therapy, corticosteroids are sometimes given to patients at a higher risk of IVIG non-responsiveness. In this study, we examined the effect of IVIG and corticosteroids in U937 derived M1 and M2 a macrophages.

Methods: A total of 40 children with KD and 30 healthy controls were enrolled. U937-derived macrophages were stimulated with patient plasma to examine its effect on macrophage polarization. U937 derived M1 and M2 macrophages were then stimulated with IVIG and methylprednisolone. RNA was extracted from cell cultures and the expression levels of STAT1, interleukin (IL)-1β, PPARγ and IL-10 were determined by RT-PCR.

Results: IVIG was effective at suppressing IL-10 expression in M2 macrophages (relative mRNA expression mean ± SE, high dose IVIG Vs. untreated 0.304 ± 0.095 Vs. 2.541 ± 0.157, p = 0.002), but did not suppress the production of IL-1β in M1 macrophages. In contrast, methylprednisolone both suppressed the IL-1β in M1 macrophages and also enhanced IL-10 in M2 macrophages even at low doses (relative mRNA expression mean ± SE, low dose methylprednisolone Vs. untreated IL-1β 6.353 ± 0.414 Vs. 93.838 ± 1.321, p < 0.001, IL-10 61.117 ± 2.319 Vs. 46.867 ± 2.893, p = 0.005).

Discussion: In this study we found that methylprednisolone was effective at suppressing the inflammatory cytokine IL-1β in M1 macrophages, and enhanced the production of anti-inflammatory IL-10 in M2 macrophages, an effect that could not be produced by IVIG. Our findings provide further mechanistic evidence that corticosteroid therapy, even at low doses may be a cost-effective adjuvant to IVIG therapy in patients with high-risk KD.