The interleukin-12-mediated pathway of immune events is dysfunctional in human immunodeficiency virus-infected individuals.
Interleukin-12 (IL-12) is a potentially critical factor in the immune response against human immunodeficiency virus (HIV) because it is important for regulating proliferation and interferon-gamma (IFN-gamma) production by T cells and natural killer (NK) cells, antigen presentation and accessory cell function by macrophages and dendritic cells, and cytolytic activities of cytotoxic T-lymphocyte cells and NK cells, which are all functions known to be dysfunctional in patients with acquired immune deficiency syndrome. Peripheral blood mononuclear cells (PBMC) from HIV-infected patients have been previously shown to be deficient in the ability to produce IL-12 in response to the bacterial pathogen Staphylococcus aureus Cowan. In this study, impaired IL-12 production in cells from PBMC of HIV-infected patients compared with healthy donors was observed across a broad panel of stimuli derived from infectious pathogens with or without priming with cytokines such as IFN-gamma and IL-4, which amplify the IL-12 induction signal. Analysis of p40 and p35 mRNA accumulation showed that reductions in both subunits contribute to the lower IL-12 secretion of cells from HIV-infected individuals. PBMC from HIV-infected donors also failed to upregulate the IL-12 receptor beta2 chain (IL-12Rbeta2) in response to mitogenic stimuli. The expression of the IL-12Rbeta2 gene could, however, be restored by in vitro exposure to rIL-12. Thus, it is possible that a primary IL-12 defect may lead to secondary deficiencies in expression of the genes for IL-12Rbeta2 and IFN-gamma, thus amplifying immune deficiency during HIV infection.
Marshall
J D
JD
Wistar Institute of Anatomy and Biology, Division of Immunologic and Infectious Diseases of the Children's Hospital of Philadelphia, PA 19104, USA.
Chehimi
J
J
Gri
G
G
Kostman
J R
JR
Montaner
L J
LJ
Trinchieri
G
G
D000328:Adult; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D018123:Receptors, Interleukin / Q000276:immunology*; D053707:Receptors, Interleukin-12; D013203:Staphylococcal Infections / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology*
C508439:IL12RB2 protein, human; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12