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Infection and Immunity, April 2001, p. 2470-2476, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2470-2476.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Down-Regulation of Interleukin-8 Secretion from Mycobacterium tuberculosis-Infected Monocytes by Interleukin-4 and -10 but Not by Interleukin-13

Clara Ameixadagger and Jon S. Friedland*

Department of Infectious Diseases, Imperial College of Science, Technology and Medicine, Hammersmith Campus, London, United Kingdom

Received 13 October 2000/Returned for modification 25 November 2000/Accepted 16 January 2001

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 TH2-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 µM 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-kappa B. 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.

* Corresponding author. Mailing address: Dept. of Infectious Diseases, Imperial College of Science, Technology & Medicine, Hammersmith Hospital, Du Cane Rd., London W12 ONN, United Kingdom. Phone: 44 20 8383 8521. Fax: 44 20 8383 3394. E-mail: j.friedland{at}ic.ac.uk.

dagger Present address: The Wolfson Institute for Biomedical Research, London WC1E 6AU, England.

Infection and Immunity, April 2001, p. 2470-2476, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2470-2476.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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