Recent discoveries of interleukin (IL)-23, its receptor, and its signal-transduction pathway add to our understanding of cellular immunity. IL-23 is a heterodimer, comprising IL-12 p40 and the recently cloned IL-23-specific p19 subunit. IL-23 uses many of the same signal-transduction components as IL-12, including IL-12Rbeta1, Janus kinase 2, Tyk2, signal transducer and activator of transcription (Stat)1, Stat3, Stat4, and Stat5. This may explain the similar actions of IL-12 and IL-23 in promoting cellular immunity by inducing interferon-gamma production and proliferative responses in target cells. Additionally, both cytokines promote the T helper cell type 1 costimulatory function of antigen-presenting cells. IL-23 does differ from IL-12 in the T cell subsets that it targets. Whereas IL-12 acts on naïve CD4+ T cells, IL-23 preferentially acts on memory CD4+ T cells. This review summarizes recent advances regarding IL-23, providing a functional and mechanistic basis for the unique niche that IL-23 occupies in cellular immunity.

Anthrax lethal toxin (LT) is a critical virulence factor that cleaves and inactivates MAPK kinases (MAPKKs) in host cells and has been proposed as a therapeutic target in the treatment of human anthrax infections. Despite the potential use of anti-toxin agents in humans, the standard activity assays for anthrax LT are currently based on cytotoxic actions of anthrax LT that are cell-, strain-, and species-specific, which have not been demonstrated to occur in human cells. We now report that T cell proliferation and IL-2 production inversely correlate with anthrax LT levels in human cell assays. The model CD4+ T cell tumor line, Jurkat, is a susceptible target for the specific protease action of anthrax LT. Anthrax LT cleaves and inactivates MAPKKs in Jurkat cells, whereas not affecting proximal or parallel TCR signal transduction pathways. Moreover, anthrax LT specifically inhibits PMA/ionomycin- and anti-CD3-induced IL-2 production in Jurkat cells. An inhibitor of the protease activity of anthrax LT completely restores IL-2 production by anthrax LT-treated Jurkat cells. Anthrax LT acts on primary CD4+ T cells as well, cleaving MAPKKs and leading to a 95% reduction in anti-CD3-induced proliferation and IL-2 production. These findings not only will be useful in the development of new human cell-based bioassays for the activity of anthrax LT, but they also suggest new mechanisms that facilitate immune evasion by Bacillus anthracis. Specifically, anthrax LT inhibits IL-2 production and proliferative responses in CD4+ T cells, thereby blocking functions that are pivotal in the regulation of immune responses.

Anthrax lethal toxin (LT), a critical virulence factor for Bacillus anthracis, has been demonstrated to cleave and to inactivate mitogen-activated protein kinase kinases (MAPKKs) that propagate prosurvival signals in macrophages (1-5). Whether this action of anthrax LT leads to the production of proinflammatory cytokines by macrophages has been more controversial (6, 7). We now report that anthrax LT treatment leads to the specific extracellular release of interleukin (IL)-1␤ and IL-18 by the murine macrophage cell lines, RAW264.7 and J774A.1. Studies of the processing of IL-1␤ reveal that the levels of activated/cleaved IL-1␤ in RAW264.7 and J774.A1 cells are increased following treatment with anthrax LT. Enhanced processing of IL-1␤ directly correlates with increased levels in the activation of its upstream regulator, IL-1␤-converting enzyme/Caspase-1 (ICE). The extracellular release of IL-1␤ and IL-18 in response to anthrax LT is ICE-dependent, as an ICEspecific inhibitor blocks this process. These data indicate that ICE, IL-1␤, and IL-18 are downstream effectors of anthrax LT in macrophages, providing the basis for new bioassays for anthrax LT activity and representing potential therapeutic targets.Patients with anthrax infection recognized at late stages have high mortality even with appropriate antibiotic therapy (8), which is likely due to the effects of bacterial toxins that persist following death of the pathogen. One of these toxins, anthrax LT, 1 comprises anthrax protective antigen (PA) and anthrax lethal factor (LF). Anthrax PA binds target cells and allows entry of the enzymatically active anthrax LF (9). LF, in turn, inactivates mitogen-activated protein kinase kinases (MAPKKs) through cleavage at specific recognition sites (1-5).MAPKKs are critical intermediates in signal transduction cascades that ultimately lead to activation of the NF-B family of transcription factors that promote macrophage survival (4). Although some of the elements underlying the mechanism of action of anthrax LT-induced apoptosis have now been elucidated, the etiology of species-and cell-specific differences in sensitivity to anthrax LT remains unclear. In addition, the role of other downstream effectors, such as cytokines, is disputed. In this regard, seemingly contradictory reports have been published that either support or reject roles for proinflammatory cytokines in responses to anthrax LT in vitro (6 -7). We now report that anthrax LT treatment induces rapid activation of ICE, a caspase family enzyme responsible for the processing of IL-1␤ and IL-18 into active forms. Anthrax LT treatment results in the extracellular release of IL-1␤ and IL-18 by murine macrophage cell lines in a manner dependent upon the activation of ICE. Studies of the action of anthrax lethal toxin on the regulation of IL-1␤ reveal that anthrax lethal toxin likely enhances both the cleavage of cytokine proforms and the release of intracellular stores of preprocessed cytokine. These data provide the basis for developing new anthrax LT bioassays an...

Platelet factor 4 (CXCL4), a member of the CXC chemokine subfamily released in high amounts by activated platelets, has been identified as a monocyte survival factor that induces monocyte differentiation into macrophages. Although CXCL4 has been shown to have biological effects unique to chemokines, nothing is known about the role of CXCL4-derived human macrophages or CXCL4 in human immunodeficiency virus (HIV) disease. In this study, CXCL4-derived macrophages are compared with macrophage-colony stimulating factor (M-CSF)-derived macrophages for their ability to support HIV-1 replication. We show that CXCL4-derived macrophages can be infected with macrophage-tropic HIV-1 that uses either CC-chemokine receptor 5 (CCR5) or CXC-chemokine receptor 4 (CXCR4) as a co-receptor for viral entry. We also find that M-CSF and the chemokines, monocyte chemoattractant protein 1 (MCP-1; CCL2) and macrophage-inflammatory-protein-1-alpha (MIP-1alpha; CCL3) are produced upon R5- and X4-tropic HIV-1 replication in both M-CSF- and CXCL4-derived human macrophages. In addition, CXCL4 added to M-CSF-derived macrophages after virus adsorption and maintained throughout the infection enhances HIV-1 replication. We thus propose a novel role for CXCL4 in HIV disease.