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Journal of Virology, December 2002, p. 12448-12456, Vol. 76, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.24.12448-12456.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Elevated Levels of Circulating Interleukin-18 in Human Immunodeficiency Virus-Infected Individuals: Role of Peripheral Blood Mononuclear Cells and Implications for AIDS Pathogenesis

Rasheed Ahmad,1 Sardar T. A. Sindhu,1 Emil Toma,2 Richard Morisset,2 and Ali Ahmad1*

Laboratory of Immunovirology, Pediatric Research Center, and Department of Microbiology and Immunology, University of Montreal and Sainte-Justine Hospital, Montreal, Quebec, Canada H3T 1C5,1 Department of Microbiology and Immunology, University of Montreal and Hôtel-Dieu Hospital, Montreal, Quebec, Canada H2W 1T82

Received 17 June 2002/ Accepted 13 September 2002

Originally identified as the gamma interferon-inducing factor, interleukin-18 (IL-18) was rediscovered as a proinflammatory cytokine related to the IL-1 family of cytokines that plays an important role in both innate and adaptive immune responses against viruses and intracellular pathogens. Despite its importance in inducing and regulating immune responses, relatively little is known about its production in HIV infection. We report here significantly (P < 0.05) elevated levels of this cytokine in the sera of human immunodeficiency virus (HIV)-infected/AIDS patients compared to those of HIV-seronegative healthy persons. Surprisingly, the peripheral blood mononuclear cells (PBMC) from HIV-infected/AIDS patients were compromised in the ability to upregulate IL-18 gene expression and produce this cytokine with and without lipopolysaccharide (LPS) stimulation. A significant positive correlation (P < 0.05) existed between the concentration of IL-18 in serum and its production from PBMC of HIV-seronegative healthy individuals but not those of HIV-infected/AIDS patients. Furthermore, the patients' PBMC expressed relatively reduced levels of activated caspase-1 constitutively as well as in response to LPS stimulation. Our data suggest the involvement of transforming growth factor beta (TGF-ß) in suppressing IL-18 production from the patients' PBMC for the following reasons. (i) In in vitro studies it suppressed the production of IL-18 from PBMC. (ii) Its levels were significantly higher in the plasma of patients compared to that of control subjects. (iii) A significant negative correlation existed between the concentrations of TGF-ß in plasma and of IL-18 in serum of the patients. The elevated levels of IL-18 in the serum of HIV-infected individuals may contribute to AIDS pathogenesis, whereas its compromised production from their PBMC in response to stimuli may reduce their innate defense to opportunistic intracellular pathogens.

* Corresponding author. Mailing address: Laboratory of Immunovirology, Sainte-Justine Hospital, 3175 Côte Ste-Catherine, Montréal, Québec, Canada H3T 1C5, Tel: (514) 345-4729, Fax: (514) 345-4801, E-mail: ahmada{at}justine.umontreal.ca.

Journal of Virology, December 2002, p. 12448-12456, Vol. 76, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.24.12448-12456.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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