Down-regulation of interleukin-8 secretion from Mycobacterium tuberculosis-infected monocytes by interleukin-4 and -10 but not by interleukin-13.
Interleukin-8 (IL-8), a CXC chemokine, has a central role in leukocyte recruitment to areas of granuloma formation in tuberculosis. In the present studies, we investigated the effect of the T(H)2-derived cytokines IL-4, IL-10, and IL-13 on Mycobacterium tuberculosis-induced IL-8 secretion from purified human monocytes. Our results demonstrate that IL-4 and IL-10 have a down-regulatory effect on IL-8 secretion and that this effect is dose dependent. IL-10 has a greater effect than IL-4 on secretion, and autologous IL-10 secreted from M. tuberculosis-infected monocytes also down-regulates IL-8 secretion. The down-regulatory effect is partly a result of reduced IL-8 mRNA accumulation analyzed by reverse transcription-PCR. When combined, 1 microM IL-4 and IL-10 had an additive effect in decreasing IL-8 secretion and transcription; there was no synergy of action. IL-13 did not have any significant effect on IL-8 gene expression or secretion. The inhibitory effect of IL-10 but not of IL-4 is associated with decreased nuclear binding of the key activating transcription factor NF-kappaB. We show for the first time that M. tuberculosis causes up-regulation of nuclear binding of Oct-1 detected by electromobility gel shift assay. However, neither AP-1 nor Oct-1 nuclear binding was altered by IL-4 or IL-10. In summary, this study demonstrates that type 2 responses have an important role in the regulation of M. tuberculosis-induced IL-8 expression but that the mechanisms by which the different cytokines act are distinct.
Department of Infectious Diseases, Imperial College of Science, Technology and Medicine, Hammersmith Campus, London, United Kingdom.
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Ameixa
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Friedland
D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D051863:Host Cell Factor C1; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism* / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D050811:Octamer Transcription Factor-1; D012333:RNA, Messenger / Q000032:analysis; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; D018793:Interleukin-13; D016209:Interleukin-8; D016328:NF-kappa B; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016753:Interleukin-10; D015847:Interleukin-4; D004247:DNA