Effect Of Cytokines In Host Defense And Inflammation

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Abstract

This year we continued our investigations of the basis for excessive granuloma formation in CGD. We showed that CGD neutrophils make two to four-fold more IL-8 chemoattractant and a sustained IL-8 mRNA response compared with normal neutrophils. Moreover, normal neutrophils treated with catalase to scavange extracellular hydrogen peroxide, or treated with diphenyleneiodonium chloride (DPI) to inhibit NADPH oxidase, exhibit IL-8 responses comparable to CGD neutrophils. In contrast, there is no difference in the fMLF-induced transient increases in IL-1a protein and IL-1a mRNA in CGD vs. normal neutrophils. In addition, fMLF fails to induce increases in IL-1a, TNF-a, IL-6, IL-1ra or other chemokines in normal neutrophils treated with either catalase or DPI. Addition of hydrogen peroxide or a hydrogen peroxide-generating system (hypoxanthine plus xanthine oxidase) suppresses the sustained IL-8 mRNA and increased protein production observed in CGD neutrophils. These results indicate that effectors downstream of the activation of NADPH oxidase negatively regulate IL-8 mRNA in normal neutrophils and their absence in CGD cells results in prolonged IL-8 mRNA transcription and enhanced IL-8 levels. This abnormal regulation of IL-8 may contribute to the excess granuloma formation in CGD. Reactive oxygen species may play a critical role in regulating inflammation through this mechanism.