Intravenous immunoglobulin and salicylate differentially modulate pathogenic processes leading to vascular damage in a model of Kawasaki disease
Abstract
Objective
Kawasaki disease (KD) is a multisystem vasculitis affecting children and is characterized by immune activation in the acute stage of disease. Systemic inflammation eventually subsides, although coronary arteritis persists, resulting in aneurysm formation. KD is the leading cause of acquired heart disease among children in North America. Accepted treatment guidelines include high-dose intravenous immunoglobulin (IVIG) and aspirin in the acute phase. Although this therapy is effective, the cellular and molecular mechanisms involved are not clear. The aim of this study was to examine the effect of IVIG and salicylate at each stage of disease development.
Methods
Using a murine model of KD, we established and validated several in vitro techniques to reflect 3 key steps involved in disease pathogenesis, as follows: thymidine incorporation to evaluate T cell activation, enzyme-linked immunosorbent assay to measure tumor necrosis factor α (TNFα) production, and real-time polymerase chain reaction to examine TNFα-mediated expression of matrix metalloproteinase 9 (MMP-9).
Results
At therapeutic concentrations, IVIG, but not salicylate, effectively reduced the immune response leading to TNFα expression. Unexpectedly, pharmacologic doses of salicylate were not able to inhibit TNFα production and in fact enhanced its production. Neither drug directly regulated MMP-9 expression but did so only indirectly via modulating TNFα. TNFα activity was a prerequisite for local expression of MMP-9 at the coronary artery.
Conclusion
Therapeutic concentrations of IVIG and salicylate differentially modulate the expression of TNFα and its downstream effects. Further dissection of the biologic effects of aspirin in acute KD is necessary for the rational design of therapy.
