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Published online before print May 13, 2005

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(Journal of Leukocyte Biology. 2005;78:544-554.)
© 2005 by Society for Leukocyte Biology

Escherichia coli K1 inhibits proinflammatory cytokine induction in monocytes by preventing NF-B activation

Suresh K. Selvaraj^* and Nemani V. Prasadarao^*,,1

^* Division of Infectious Diseases, The Saban Research Institute, Childrens Hospital Los Angeles, and
Keck School of Medicine, University of Southern California, Los Angeles

¹ Correspondence: Division of Infectious Diseases, MS #51, The Saban Research Institute, Childrens Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027. E-mail: pnemani{at}chla.usc.edu

Phagocytes are well-known effectors of the innate immune system to produce proinflammatory cytokines and chemokines such as tumor necrosis factor (TNF-), interleukin (IL)-1ß, and IL-8 during infections. Here, we show that infection of monocytes with wild-type Escherichia coli K1, which causes meningitis in neonates, suppresses the production of cytokines and chemokines (TNF-, regulated on activation, normal T expressed and secreted, macrophage-inflammatory protein-1ß, IL-1ß, and IL-8). In contrast, infection of monocytes with a mutant E. coli, which lacks outer membrane protein A (OmpA– E. coli) resulted in robust production of cytokines and chemokines. Wild-type E. coli K1 (OmpA+ E. coli) prevented the phosphorylation and its degradation of inhibitor of B, thereby blocking the translocation of nuclear factor (NF)-B to the nucleus. OmpA+ E. coli-infected cells, subsequently subjected to lipopolysaccharide challenge, were crippled severely in their ability to activate NF-B to induce cytokine/chemokine production. Selective inhibitors of the extracellular signal-regulated kinase (ERK) 1/2 pathway and p38 mitogen-activated protein kinase (MAPK), but not Jun N-terminal kinase, significantly reduced the activation of NF-B and the production of cytokines and chemokines induced by OmpA– E. coli, indicating a role for these kinases in the NF-B/cytokine pathway. It is interesting that the phosphorylation of ERK 1/2 and p38 MAPK was notably reduced in monocytes infected with OmpA+ E. coli when compared with monocytes infected with OmpA– E. coli, suggesting that the modulation of upstream events common for NF-B and MAPKs by the bacterium is possible. The ability of OmpA+ E. coli K1 to inhibit the macrophage response temporarily may enable bacterial survival and growth within the host for the onset of meningitis by E. coli K1.

Key Words: meningitis • OmpA • phagocytosis • inflammation • MAP kinases

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