In previous studies, we have found that anthrax lethal toxin (LeTx) induces apoptosis in both murine macrophages and human peripheral blood mononuclear cells (PBMCs). In this study, we further report that bacterial cell wall (CW) components of Bacillus (B.) anthracis are powerful inducers of proinflammatory cytokines from the PBMCs. These effects are deprived when the LeTx is present. The major causative element for this suppression is lethal factor (LF) rather than protective antigen (PA). These results indicate that the roles of LeTx in anthrax pathogenesis, particularly its effects on cytokine production, should be reevaluated as our findings and other reports are controversial to the conventional concept. 1. Introduction Anthrax is initiated by infection with B. anthracis, a Gram-positive, spore forming bacterium. Infection occurs through three primary routes: cutaneous, ingestion, and inhalation of the spores. Systemic infection by inhalation of the spores has become a major research focus due to several reasons. First and foremost is the likelihood that B. anthracis spores would be used as a biological weapon due to its ease of growth, long shelf life, stability in the environment, and the ability to be effectively disseminated in a large area to inflict high mortality. Furthermore, the inhalation form can cause septic shock that has a mortality rate approaching 100% with death occurring within a few days after onset of symptoms if vigorous treatment is not given immediately after exposure. Lastly, to date, there is no effective treatment for the late-stage infection and it is usually fatal, even with aggressive antibiotic therapy [1]. Therefore, given these factors, in conjunction with the increased threat of a biological attack, it is imperative that the true pathogenesis of this microbe should be understood so that new successful treatment methods can be developed. The virulence of B. anthracis depends on three plasmid-encoded factors: two secreted protein toxins and an antiphagocytic poly-D-glutamic acid capsule. The two toxins, collectively called anthrax toxin, are formed by the binary association of three proteins: PA (83？kDa), LF (90？kDa), and edema factor (EF, 89？kDa). PA either combines with LF to form lethal toxin (LeTx) or with EF to form edema toxin (EdTx) [2–4]. LeTx is considered to be responsible for the lysis of macrophages, which is accompanied by the release of cytokines, specifically tumor-necrosis-factor (TNF-) α and interleukin- (IL-) 1β. These cytokines are considered to be the major players responsible for septic shock, and
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