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(Journal of Leukocyte Biology. 2000;68:383-390.)
© 2000 by Society for Leukocyte Biology

Proinflammatory response and IL-12 expression in HIV-1 infection

Xiaojing Ma and Luis J. Montaner

The Wistar Institute, Philadelphia, Pennsylvania

Correspondence: Dr. L. J. Montaner, Director HIV-1 Immunopathogenesis Lab, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. E-mail: montaner{at}wistar.upenn.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PRODUCTION OF IL-12
 MODULATION OF IL-12 PRODUCTION
 MOLECULAR CONTROL OF IL-12...
 TNF-{alpha}-MEDIATED...
 CONCLUDING REMARKS
 REFERENCES
 
HIV-1 infection elicits a broad range of host responses, many of which interfere with the regulatory pathways of gene expression of interleukin-12 (IL-12), a heterodimeric cytokine essential for cell-mediated immunity against microbial infection. The inhibition of IL-12 production by accessory cells after HIV-1 infection has been identified as a potential factor responsible for impaired innate and Th1 cell-mediated responses observed in AIDS patients. The mechanism by which HIV-1 infection suppresses IL-12 gene expression is largely uncharacterized. Here we review all pathways identified that could potentially mediate HIV-induced impairment of IL-12 gene expression, such as IL-10, transforming growth factor ß, interferon-{alpha}/ß, tumor necrosis factor {alpha}, Fc receptors, complement regulatory proteins, and receptors. Also discussed is the decreased CD40 ligand induction in CD4 T cells during HIV infection, which may have a strong impact on T cell-dependent IL-12 production that is critical for the establishment and maintenance of a Th1 response.

Key Words: transforming growth factor ß • interferon • tumor necrosis factor {alpha}


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PRODUCTION OF IL-12
 MODULATION OF IL-12 PRODUCTION
 MOLECULAR CONTROL OF IL-12...
 TNF-{alpha}-MEDIATED...
 CONCLUDING REMARKS
 REFERENCES
 
Production of proinflammatory cytokines by phagocytic cells during an infection is essential for the activation of the effector cells of innate resistance. The early inflammatory responses are also an integral part of the process of generating antigen-specific effector cells of adaptive immunity. Interleukin-12 (IL-12) plays a major role in bridging the two phases of immunity. IL-12 is a heterodimer produced by phagocytic and antigen-presenting cells in both innate and adaptive immune responses. It is a key factor in the induction of T cell-dependent and -independent activation of macrophages, generation of T helper type 1 (Th1) and cytotoxic T cells, suppression of IgG1 and IgE production, induction of organ-specific autoimmunity, and resistance to bacterial and parasitic infections [1 ]. The genes encoding the two chains of IL-12, p40 and p35, are located on different human chromosomes. Together, p40 and p35 form the biologically active IL-12. Their expressions are highly coordinated during an effective immune response.

HIV infection is characterized by a variety of disturbances in the regulation of cytokine expression. These disturbances include a general decrease in the expression of type 1 T-helper cytokines, an increase in expression of proinflammatory cytokines, a possible increase in type 2 helper cytokines, and increased expression of antiviral interferons and transforming growth factor ß (TGF-ß) [2 3 4 5 ]. These perturbations may contribute to HIV disease pathogenesis by contributing to the impaired cellular immune responses and cell loss that characterize HIV infection and AIDS and by accelerating replication of HIV-1. Moreover, in HIV infection, peripheral mononuclear cells (PBMC) from HIV-1-infected patients have been shown to produce significantly less IL-12 than those from uninfected controls [6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 ] (see Table 1 ). This may have strong implications in the subdued ability of the patients to mount a strong cellular immune response against the virus.


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  		Table 1. Effects of HIV-1 Infection on IL-12 Production

 

   PRODUCTION OF IL-12
TOP
 ABSTRACT
 INTRODUCTION
 PRODUCTION OF IL-12
MODULATION OF IL-12 PRODUCTION
 MOLECULAR CONTROL OF IL-12...
 TNF-{alpha}-MEDIATED...
 CONCLUDING REMARKS
 REFERENCES
 
IL-12 was originally discovered and characterized as a product of the Epstein-Barre virus (EBV)-transformed lymphoblastoid B cell lines RPMI-8866, ADP, and NC37 [27 ]. Phagocytic cells, however, have been subsequently and firmly established as a major source of IL-12 production by many in vitro and in vivo studies in infectious disease models [28 ]. PBMC or purified monocytes produce high levels of IL-12 p40 and p70 when stimulated by bacteria, such as heat-fixed Staphylococcus aureus or Staphylococcus extracts, or by bacterial products such as lipopolysaccharide (LPS). The producer cells within PBMC are mostly monocytes and other MHC class II-positive cells such as dendritic cells. The production of IL-12 by phagocytic cells, and at least in part by dendritic cells, is induced by a variety of mechanisms that reflect the role played by IL-12 in inflammation and immunity. These mechanisms are either T cell-independent or -dependent. The T cell-independent mechanisms are important for the proinflammatory and immunoregulatory role of IL-12 at the interface of innate resistance and adaptive immunity. These mechanisms are exemplified by the induction of IL-12 by infectious agents such as bacteria, both protozoan and metazoan parasites, fungi, and viruses as well as their products, of which LPS and bacterial DNA are the most typical examples [29 ]. During inflammation, however, an important mechanism of pathogen-independent induction of IL-12 and other cytokines is represented by interaction of adhesion molecules with substrates of inflammatory origin, exemplified by the interaction of CD44 adhesion molecules with low-molecular-weight fragments of the extracellular matrix glycosaminoglycan hyaluronan (LMW-HA) that accumulate in inflammation [30 ]. The T cell-dependent mechanism of IL-12 production is dependent on the ability of CD40 ligand (CD40L) expressed on activated T cells to interact with CD40 receptor on the surface of monocyte/macrophages and dendritic cells [19 , 31 32 33 34 35 36 ]. The T cell-dependent mechanisms of IL-12 induction play an important role in the T cell immunoregulatory role of IL-12 and in particular in the maintenance of Th1 responses [31 , 37 38 39 40 41 ].


   MODULATION OF IL-12 PRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
 PRODUCTION OF IL-12
 MODULATION OF IL-12 PRODUCTION
MOLECULAR CONTROL OF IL-12...
 TNF-{alpha}-MEDIATED...
 CONCLUDING REMARKS
 REFERENCES
 
IL-12 production during an immune reaction is tightly modulated by both positive and negative feedback signals. The positive feedback regulation is exemplified by interferon-{gamma} (IFN-{gamma}), which is induced by IL-12 initially from natural killer (NK) and T cells and which in turn potently enhances the ability of monocytes and polymorphonuclear cells (PMN) to produce IL-12 [42 ]. The priming effect of IFN-{gamma} for augmented IL-12 production may represent a mechanism in which IL-12-induced Th1 responses are maintained in vivo. This effect is substantiated only after extended treatment of monocytes with IFN-{gamma} (>8 h optimally) before stimulation with bacterial products such as LPS, suggesting that it may be secondary to an activation/maturation/differentiation effect induced by IFN-{gamma}. The positive feedback amplification of IL-12 production mediated by IFN-{gamma} is a potentially dangerous mechanism leading to uncontrolled cytokine production and possibly shock. There are also effective mechanisms that down-regulate IL-12 production and the responsiveness of T and NK cells to IL-12. The type-2 cytokine IL-10 is a potent inhibitor of IL-12 production from phagocytic cells; the ability of IL-10 to suppress production of IFN-{gamma} and other Th1 cytokines is due primarily to its inhibition of IL-12 production from antigen-presenting cells (APC) and to its inhibition of expression of other costimulatory surface molecules (e.g., B7) and soluble, proinflammatory cytokines [e.g., tumor necrosis factor {alpha} (TNF-{alpha}), IL-1ß] [43 , 44 ]. Another powerful inhibitor of IL-12 production is TGF-ß, a product of activated platelets, macrophages, and malignant tumors [45 , 46 ]. Type I interferons (IFN-{alpha}/ß) are also potent inhibitors of APC-derived IL-12 production, both T cell-dependent and -independent [47 48 49 50 ]. HIV infection often results in the overexpression of these immunosuppressive agents and concomitant impairment of IL-12 and IFN-{gamma} production from accessory and effector cells [2 , 5 , 7 , 8 , 10 , 13 , 17 , 22 , 24 , 51 52 53 54 ].

An important mechanism of regulation of IL-12 during innate resistance and adaptive immunity is represented in the ability of complement components and immunoglobulins to act as negative regulators of IL-12 production. The first indication that IL-12 production is also regulated by complement was provided by the observation that measles virus induces a profound depression of Th1 responses after infection, in part by interacting with its receptor on phagocytic cells, the CD46 molecule, to inhibit IL-12 production [55 ]. CD46, or membrane cofactor protein, is a binding site for C3b and C4b. By binding to CD46, both polymeric C3b or anti-CD46 antibodies can inhibit IL-12 production, suggesting that measles virus may utilize a physiological mechanism of selectively down-regulating IL-12 through activated complements in its induction of immunosuppression. HIV activates the complement system in human plasma and may interact with complement regulatory molecules for its own advantage in addition to inhibiting IL-12: enhancement of infectivity, follicular localization, and broadening of its host range while displaying an intrinsic resistance against the lytic action of human complement [56 , 57 ].

Immunocomplexes occur in a number of chronic human diseases that otherwise would be controlled by Th-1 type immune responses, such as in HIV-infection, tuberculosis, and malignant processes [58 , 59 ]. The ability to trigger monocyte/macrophage receptors and selectively suppress IL-12 production was first observed in the interaction of C3bi with complement receptor 3 (CD11b) and that of immunocomplexes with FcR or scavenger receptors [60 61 62 ]. CD11b and FcR have also been shown to interact with each other and synergize in functional activation of the effector cells, suggesting possible converging signal transduction pathways [63 64 65 66 ]. The FcR-mediated inhibition of IL-12 is interesting because cross-linking of these receptors is also a potent stimulus for the induction of other proinflammatory cytokines [67 68 69 70 71 72 73 74 75 ]. This phenomenon may be related to the notion that aggregating FcR may result in both positive and negative signals, depending on the types of FcR that are interacting. For instance, interaction between FcR containing immunoreceptor tyrosine-based activating motif (ITAM) and FcR containing immunoreceptor tyrosine-based inhibitory motif (ITIM) results in negative cooperation [76 ]. Calcium fluxes and the production of prostaglandin E2 are implicated in FcR-mediated inhibition of IL-12 production. IL-10 and TNF-{alpha} are partially responsible for this inhibition because it has been demonstrated that the use of anti-IL-10 and anti-TNF-{alpha} antibodies resulted in an incomplete reversal of the suppression of IL-12 production mediated by immunocomplexes or FcR ligation [62 ]. This cytokine down-regulation after receptor ligation may contribute to the transient nature of IL-12 in plasma during bacteremia, and it may result in diminished IL-12 production in an immune host due to the rapid clearance of IgG-opsonized bacteria. The receptor-mediated inhibition of IL-12 induction may also be exploited by intracellular pathogens of macrophages to down-regulate IL-12 production and suppress or delay the development of cell-mediated immunity.

The interaction between CD40 on APC and CD40L on CD4 T cells and subsequent induction of IL-12/IFN-{gamma} production are thought to be vitally important for the initiation and maintenance of antigen-specific type I immune response, and essential for protective immunity against some intracellular pathogens including Leishmania, Toxoplasma, and Mycobacteria, all of which are well-known opportunistic pathogens in AIDS patients [44 , 77 78 79 80 81 ]. Present data suggest that in the asymptomatic stage of AIDS progression the capacity of the CD4 T cells to up-regulate CD40L is preserved and IL-12 production by APC upon CD40 triggering is increased. At later stages, in contrast, both the low number of antigen-specific CD4 T cells and their dramatically impaired CD40 L expression preclude efficient IL-12 induction [25 ].

Clearly, the understanding of the molecular mechanisms of positive and negative modulation of IL-12 by these immunologic molecules has direct relevance to our strategies to remedy immune dysfunction. Currently, numerous pathways have been identified by which IL-12 production from macrophages and dendritic cells is regulated. These are summarized in Figure 1 .



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  		Figure 1. Positive and negative regulators of IL-12 production. Most of the known pathways that lead to the stimulation (+) or repression (-) of IL-12 production by macrophages are depicted.

 

   MOLECULAR CONTROL OF IL-12 GENE EXPRESSION
TOP
 ABSTRACT
 INTRODUCTION
 PRODUCTION OF IL-12
 MODULATION OF IL-12 PRODUCTION
 MOLECULAR CONTROL OF IL-12...
TNF-{alpha}-MEDIATED...
 CONCLUDING REMARKS
 REFERENCES
 
The analysis of the molecular control of IL-12 production is complicated by the need to study the coordinated expression of both p40 and p35 genes. The p40 gene is highly inducible and expressed only in IL-12-producing cells, compared with that of the more ubiquitously expressed p35 gene. Simultaneous analysis of nuclear transcription, steady-state mRNA, and secreted protein levels of IL-12, has established that the human IL-12 p40 gene is primarily regulated at the transcriptional level by IFN-{gamma} and LPS in monocytic cells [42 ]. Both the human and mouse IL-12 p40 promoters have been cloned [42 , 82 ]. The 3.3-kb human p40 promoter, when linked to a luciferase reporter gene, transiently or stably transfected into various IL-12-producing and non-producing cell lines, has largely recapitulated the cell specificity of the endogenous p40 gene, i.e., it is constitutively active in EBV-transformed B cell lines (e.g., RPMI-8866, CESS), and inducible by LPS in myeloid cell lines (e.g., THP-1 and RAW 264.7), but inactive in T cell lines (e.g., Molt-13 and Jurkat) [42 ]. Moreover, this promoter construct responds to IFN-{gamma} priming in monocytic cells much like the endogenous p40 gene, suggesting that it contains sufficient sequence elements to reconstitute the in vivo response [42 ]. A detailed functional dissection of the human p40 promoter in monocytic and EBV-B cell lines has identified two critical cis-elements involved in the regulation of the p40 gene transcription by LPS and IFN-{gamma}. An ets site at -211/-206 (TTTCCT) and an NF-{kappa}B half site at -117/-107 (TGAAATTCCCC). The ets site and its surrounding sequences (-292/-196) interacts with a very large complex named F1, which is induced by either LPS or IFN-{gamma} and that is composed of ets-2, IRF-1, NF-{kappa}B c-Rel, and a novel, ets-2-related protein [83 ]. The "NF-{kappa}B half site" binds p50/p65 and p50/c-Rel heterodimers induced by LPS [82 , 84 ]. Both elements are essential because deletion or mutation of specific nucleotides within these sites abolish the p40 promoter activity.

The presence of IRF-1 in the F1 complex, thereby its involvement in the regulation of p40 gene expression, is strongly supported by the observation of deficient IL-12 production and impaired Th-1 responses in IRF-1-null mice [85 ]. HIV infection frequently leads to deficiencies in IFN-{gamma} production and/or responses [23 , 52 , 86 , 87 ], which would secondarily affect the synergistic activation of IL-12 production mediated by IFN-{gamma}. Another gene that is induced by IFN-{gamma} is the interferon consensus binding protein (ICSBP), which belongs to the IRF family of transcription factors but which is expressed exclusively in cells of the immune system. Mice with a disrupted ICSBP gene are selectively deficient in IL-12 p40 gene expression and highly susceptible to infection with intracellular pathogens such as Listeria monocytogenes and T. gondii [88 ]. The ets site in the p40 promoter bears strong resemblance to the ISRE that ICSBP interacts with. Our functional studies indicate that ICSBP can act through this site and synergize specifically with IRF-1 to activate the human p40 promoter in cells of the macrophage lineage [Wang et al., unpublished results].

Our current working model on the regulation of human IL-12 p40 gene expression in monocytic cells is illustrated in Figure 2 . This model incorporates the present knowledge of LPS- and IFN-{gamma}-induced signals that produce the synergistic activation of the p40 promoter.



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  		Figure 2. Model of the activation of the human IL-12 p40 gene promoter in macrophages. LPS and IFN-{gamma} induce two separate pathways that converge on the IL-12 p40 promoter through the NF-{kappa}B and ets sites. LPS also activates the MAPK p38. However, how exactly p38 activation and phosphorylation contributes to the IL-12 p40 transcription is unknown. It may converge with the LPS pathway or the INF-{gamma} pathways, or through an independent pathway. The numbers beneath the bar representing the p40 promoter refer to the respective coordinates of each of the functional promoter elements depicted. The F2 factor binding at the ets site is an unidentified activity.

 

   TNF-{alpha}-MEDIATED INFLAMMATION AND IL-12 GENE EXPRESSION
TOP
 ABSTRACT
 INTRODUCTION
 PRODUCTION OF IL-12
 MODULATION OF IL-12 PRODUCTION
 MOLECULAR CONTROL OF IL-12...
 TNF-{alpha}-MEDIATED...
CONCLUDING REMARKS
 REFERENCES
 
TNF-{alpha} is one of the principle mediators of inflammatory responses in mammals [89 ]. In addition to its well-known role in septic shock, it has been implicated in the pathogenesis of chronic processes such as autoimmunity [90 ], graft-versus-host disease [91 ], rheumatoid arthritis [92 ], Crohn’s disease [93 ], and the cachexia accompanying cancer [94 ] and acquired immunodeficiency syndrome (AIDS) [5 ]. HIV infection in vivo and in vitro is correlated with an enhanced production of TNF-{alpha} [53 , 95 96 97 98 99 100 ], coincidental with an impaired IL-12 production. Recently it was shown that IL-12 production in thioglycolate-elicited mouse macrophages could be suppressed by TNF-{alpha} and that TNF-{alpha}-deficient mice developed a delayed but vigorous inflammatory response to heat-killed Corynebacterium parvum with high levels of serum IL-12 production resulting in death [30 , 101 ]. The prompt resolution of C. parvum-injected wild type mice with lower IL-12 production suggests that TNF-{alpha} may also play a role in limiting the extent and duration of murine inflammatory responses. The role of TNF-{alpha} in human pro-inflammatory diseases and the pivotal importance of IL-12 in innate and adaptive cell-mediated responses underscores the importance of understanding TNF-{alpha} mechanisms of action in inhibiting pathogen-induced IL-12 production by macrophages. Our recent data indicate that TNF-{alpha} is a potent inhibitor of IL-12 p40 and p70 secretion from human monocytes, independently of IL-10 (Fig. 3 ) [102 ].



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  		Figure 3. Inhibition of IL-12 p40 and p70 production by TNF-{alpha} in human monocyte-derived macrophages. Macrophages were pretreated for 20 h with TNF-{alpha} at various concentrations (ng/mL), as indicated, in the presence or absence of 10 mg/mL of a neutralizing anti-IL-10 antibody (12G8) or an irrelevant isotype control (C20.8), followed by IFN-{gamma} priming (16 h), and subsequently S. aureus stimulation (24 h). Cell-free supernatants were measured for IL-12 p40 and p70 secretion by radioimmunoassay. Data (mean ± SEM) are from four donors.

 
Overall, HIV infection is associated with the induction of proinflammatory cytokines such as TNF-{alpha} and type I interferons [103 104 105 ], and with other types of immune responses such as the formation of immune complexes, thus conceivably able to utilize these cellular mechanisms to inhibit IL-12 production and signaling, hence cell-mediated immunity.


   CONCLUDING REMARKS
TOP
 ABSTRACT
 INTRODUCTION
 PRODUCTION OF IL-12
 MODULATION OF IL-12 PRODUCTION
 MOLECULAR CONTROL OF IL-12...
 TNF-{alpha}-MEDIATED...
 CONCLUDING REMARKS
REFERENCES
 
HIV infection elicits a broad range of cellular responses, many of which interfere with the regulatory pathways of IL-12 gene expression, including the acute activation of type I Interferons, chronic stimulation of TNF-{alpha} gene expression, and prostaglandin E2 production in phagocytic and effector T cells, as well as the induction of immune complexes (Table 2 ). In addition to other potential mechanisms of IL-12 inhibition, the recently identified ability of TNF-{alpha} to regulate IL-12 production by human macrophages provides direct evidence that in addition to its well-known effects in mediating the cascade of inflammatory activities in a wide array of biological responses, TNF-{alpha} signaling can selectively inhibit IL-12 gene expression upon macrophage activation as part of the scheme of cytokine feedback and self-limiting modulations. Although an inflammation-induced suppression of IL-12 may benefit the host by controlling excessive immune activation, it may also provide an immune-evasion mechanism to intracellular pathogens. It remains to be determined whether TNF-{alpha} plays a direct role in inducing a decreased IL-12 response in HIV-1 infection where sustained immune activation and production of TNF-{alpha} is associated with an impairment in IL-12 production and cell-mediated immunity. An understanding at the molecular level of the impaired IL-12 gene expression in HIV infection may reveal potential therapeutic targets for reversing immune suppression in AIDS patients.


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  		Table 2. Effects of HIV Infection on Factors Involved in the Regulation of IL-12 Production

 


   ACKNOWLEDGEMENTS
 
This work was supported in part by NIH grants CA79772 and AI45899 to X. M., and AI40379, AI44304, AI34412 to L. J. M. The authors also wish to thank the American Foundation for AIDS Research (AmFAR) for the support provided in part from Grant 02644-26-RGI.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PRODUCTION OF IL-12
 MODULATION OF IL-12 PRODUCTION
 MOLECULAR CONTROL OF IL-12...
 TNF-{alpha}-MEDIATED...
 CONCLUDING REMARKS
 REFERENCES
 

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