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Campylobacter jejuni infection of differentiated THP-1 macrophages results in interleukin 1 release and caspase-1-independent apoptosis

School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4234, USA

Correspondence
Philip F. Mixter
pmixter{at}wsu.edu

Apoptosis induction of host macrophages has emerged as a common virulence mechanism among bacterial pathogens. Infection with Campylobacter jejuni is a leading cause of gastroenteritis worldwide and is characterized by an acute inflammatory response in the small intestine. The authors used the human monocytic cell line THP-1 to examine apoptosis induction and pro-inflammatory cytokine production during C. jejuni infection. Flow cytometric analysis revealed that 48 h after inoculation, a C. jejuni wild-type isolate induced apoptosis in 63 % of THP-1 cells while only 34 % of cells inoculated with a ciaB mutant, which does not secrete the Cia (Campylobacter invasion antigens) proteins, underwent apoptosis. Complementation of the ciaB mutant resulted in levels of apoptosis similar to those induced by the C. jejuni wild-type isolate, suggesting that the Cia proteins have a role in apoptosis induction. It was shown that a proteinase K- and heat-stable component of C. jejuni also stimulated THP-1 apoptosis. Inoculation with a C. jejuni gmhD mutant indicated that lipooligosaccharide was not the stimulatory molecule. Immunoblot and ELISA analyses revealed that C. jejuni infection stimulated the synthesis, processing and secretion of interleukin 1 (IL-1). Inhibition of caspase 1 activity eliminated IL-1 processing and secretion, but did not affect apoptosis induction. In addition, treatment of cells with a caspase-9-specific inhibitor did not affect apoptosis induction, arguing against activation of an apoptotic pathway dependent on either caspase 1 or 9 activation. Collectively, these data suggest that the inoculation of macrophages with C. jejuni results in the processing of IL-1 and apoptosis through different regulatory pathways. Furthermore, these data argue that C. jejuni may use a mechanism distinct from Salmonella typhimurium and Shigella flexneri to initiate macrophage apoptosis and release of IL-1.

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