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Infection and Immunity, August 2006, p. 4430-4438, Vol. 74, No. 8
0019-9567/06/$08.00+0     doi:10.1128/IAI.00446-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Bacillus anthracis Spores Stimulate Cytokine and Chemokine Innate Immune Responses in Human Alveolar Macrophages through Multiple Mitogen-Activated Protein Kinase Pathways{dagger}

Kaushik Chakrabarty,1,{ddagger} Wenxin Wu,1,{ddagger} J. Leland Booth,1 Elizabeth S. Duggan,1 K. Mark Coggeshall,2 and Jordan P. Metcalf1,3*

Pulmonary and Critical Care Division, Department of Medicine,1 Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center,3 Programs in Immunology and Cancer, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 731042

Received 17 March 2006/ Returned for modification 20 April 2006/ Accepted 27 April 2006

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 Bacillus anthracis exposure is important in understanding the pathogenesis of this disease. In this paper, we studied the initial events after exposure to spores, beginning with the rapid internalization of spores by the macrophages. Spore exposure rapidly activated the mitogen-activated protein kinase signaling pathways extracellular signal-regulated kinase, c-Jun-NH2-terminal kinase, and p38. This was followed by the transcriptional activation of cytokine and primarily monocyte chemokine genes as determined by RNase protection assays. Transcriptional induction is reflected at the translational level, as interleukin-1{alpha} (IL-1{alpha}), IL-1ß, IL-6, and tumor necrosis factor alpha (TNF-{alpha}) cytokine protein levels were markedly elevated as determined by enzyme-linked immunosorbent assay. Induction of IL-6 and TNF-{alpha}, and, to a lesser extent, IL-1{alpha} and IL-1ß, was partially inhibited by the blockade of individual mitogen-activated protein kinases, while the 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. This report is the first comprehensive examination of this process in primary human alveolar macrophages.

* Corresponding author. Mailing address: Oklahoma University Health Sciences Center, RM 425, RP1, 800 N. Research Pkwy., Oklahoma City, OK 73104. Phone: (405) 271-1966. Fax: (405) 271-5440. E-mail: jordan-metcalf{at}ouhsc.edu.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: F. C. Fang

{ddagger} K.C. and W.W. contributed to the paper equally.

Infection and Immunity, August 2006, p. 4430-4438, Vol. 74, No. 8
0019-9567/06/$08.00+0     doi:10.1128/IAI.00446-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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