Contact with the human alveolar macrophage plays a key role in the innate immune response to Bacillus anthracis spores. Because there is a significant delay between the initial contact of the spore with the host and clinical evidence of disease, there appears to be temporary containment of the pathogen by the innate immune system. Therefore, the early macrophage response to anthrax exposure is important in understanding the pathogenesis of this disease. We examined the initial events after exposure of human alveolar macrophages obtained by bronchoscopy to Bacillus anthracis (Sterne) spores. Spores were rapidly internalized as determined by confocal microscopy. Spore exposure also rapidly activated the MAPK signaling pathways ERK, JNK, and P38. This was followed by transcriptional activation of cytokine and primarily monocyte chemokine genes as determined by RNase protection assays. Transcriptional induction was reflected at the translational level as IL-1a and b, IL-6, and TNF-a cytokine protein levels were markedly elevated as determined by ELISA. Induction of IL-6 and TNF-a, and to a lesser extent IL-1a and -b, was partially inhibited by blockade of individual mitogen-activated protein kinases, while complete inhibition of cytokine induction was achieved when multiple signaling pathway inhibitors were used. Taken together, these data clearly show activation of the innate immune system in human alveolar macrophages by Bacillus anthracis spores. The data also show that multiple signaling pathways are involved in this cytokine response.
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