OBJECTIVE

Macrophages are known to be one of the initial responders to bacterial infection. While infection of macrophages with bacteria induces apoptosis, a pro-inflammatory response is also elicited. Thus, the aim of this study is to further elucidate the differential effect of infections with bacteria on the survival and function of macrophages.

RESULTS

THP-1 monocytic cells induced to differentiate into macrophages were infected with non-pathogenic Escherichia coli (E. coli) and analyzed for apoptosis and inflammatory response over time. Following infection with E. coli macrophages underwent apoptosis which was reduced by the general caspase inhibitor, zVAD.fmk. Inhibition of caspase activity resulted in increased DNA binding activity of NF-kappaB and enhanced production of NF-kappaB-dependent reporter gene expression following infection. Increased activity of NF-kappaB was independent of IkappaBalpha since IkappaBalpha degradation was unaffected by zVAD.fmk. Further, suppression of caspase activity reduced the proteolytic cleavage of NF-kappaB. The increased activity of NF-kappaB in the zVAD.fmk-treated macrophages was associated with a markedly enhanced production of pro-inflammatory cytokines and elimination of E. coli.

CONCLUSIONS

These data indicate that infection of macrophages with E. coli induces a caspase-dependent inhibition of NF-kappaB that results in a reduced production of pro-inflammatory cytokines and impaired clearance of bacteria.