Inverse relationship of plasma prostaglandin-E2 and blood mononuclear cell cyclooxygenase-2 with disease severity in children with plasmodium falciparum malaria
Prostaglandins (PG) derived from inducible cyclooxygenase (COX-2) are important pro-inflammatory mediators of the host-immune response to infection. Since the role of host-derived PG in human malaria is unknown, plasma bicyclo-PGE2 (a stable catabolite of PGE,), and peripheral blood mononuclear cell COX-2 protein and mRNA were measured in Gabonese children with and without malaria (N=129) (see table). Relative to healthy children (N=25), bicyclo-PGE2 and COX-2 protein were lower in children with mild [p=0.007 (N=54) and 0.026 (N=19), respectively] and severe malaria [p=0.002 (N=50) and 0.010 (N=15), respectivelyJ. None of the children had ingested aspirin, and results were not influenced by a history of acetaminophen ingestion. Measurement of PBMC COX-2 mRNA showed detectable mRNA in 4/4 healthy children, 1/4 with mild malaria, and 0/4 with severe malaria. Investigation of cytokines with the potential to regulate COX-2 expression showed that IFNy, TNFa, and IL-10 significantly increased in parallel with disease severity. While IFNv and TNFa did not significantly correlate with plasma bicyclo-PGE, levels of bicyclo-PGE, and IL-10 (a cytokine known to suppress COX-2 expression) were significantly inversely correlated (P<0.001). Host resistance to malaria is promoted by pro-inflammatory cytokines such as IL-12, IFNy, and TNFa, while antiinflammatory cytokines such as IL-10 and TGFβ counter-regulate the pro-inflammatory response and may reduce resistance to disease. COX-2 expression is generally increased by pro-inflammatory cytokines and suppressed by anti-inflammatory cytokines. Based on our results, we postulate that basal PGE2 levels in healthy malaria-exposed children protects against malaria, while the IL-10-induced decreases in PGE2 during acute malaria increase susceptibility to severe disease. Future studies of PG and COX-2 in malaria should provide valuable information about disease pathogenesis, and may provide insights into the development of new treatments for this global disease. Mild Malaria Severe Malaria p value Parasitemia/uL 2770.1±4568 333772±25025 <0.0001 Hb(gm/dL) I0.3±0.3 6.8±0.3 <0.0001 Temp (°C) 38.2±0.3 39.0±0.2 <0.001 Number 54 50.
Perkins, DJ; Weinberg, JB; Kremsner, PG
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