INTERLEUKIN-4 SUPPRESSES THE EXPRESSION OF MACROPHAGE NADPH OXIDASE HEAVY-CHAIN SUBUNIT (GP91-PHOX)

The production of superoxide anion by NADPH oxidase is a principal non specific bactericidal activity of macrophages and neutrophils in host defense. However, exuberant production of superoxide anion also damage s host tissues. Cloning and DNA sequencing of the 91 kDa subunit (gp91 -phox) open reading frame indicated a high degree of sequence conserva tion, greater than 90% in nucleotide and amino acid sequences, between the porcine and human cDNAs. We show in pigs that interleukin-4 (IL-4 ), a T lymphocyte cytokine which plays a major role in mediating antib ody responses to pathogens, suppresses superoxide anion production in macrophages by specifically reducing the level of mRNA encoding gp91-p hox. Messenger RNA levels are suppressed approx. 70% within 4 h and pe rsist for 24 h without any change in the rate of mRNA turnover. Nuclea r run-on analysis showed that IL-4 did not alter the rate of gp91-phox gene transcription under conditions in which IL-1 beta transcription was inhibited. These results indicate that IL-4 suppresses the inflamm atory response of macrophages by mechanisms that include post-transcri ptional regulation of the 91 kDa catalytic subunit of NADPH oxidase, a nd transcriptional regulation of inflammatory cytokine expression.