title: Escherichia coli K1 inhibits proinflammatory cytokine induction in monocytes by preventing NF-kappaB activation.
abstract: Phagocytes are well-known effectors of the innate immune system to produce proinflammatory cytokines and chemokines such as tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, 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-alpha, regulated on activation, normal T expressed and secreted, macrophage-inflammatory protein-1beta, IL-1beta, 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 kappaB, thereby blocking the translocation of nuclear factor (NF)-kappaB to the nucleus. OmpA+ E. coli-infected cells, subsequently subjected to lipopolysaccharide challenge, were crippled severely in their ability to activate NF-kappaB 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-kappaB and the production of cytokines and chemokines induced by OmpA- E. coli, indicating a role for these kinases in the NF-kappaB/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-kappaB 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.
authors.affiliation: Division of Infectious Diseases, The Saban Research Institute, Childrens Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027, USA.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Selvaraj
authors.forename: Nemani V
authors.initials: NV
authors.lastname: Prasadarao
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D004926:Escherichia coli / Q000235:genetics / Q000276:immunology; D029968:Escherichia coli Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology; D020814:Meningitis, Escherichia coli / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D009000:Monocytes / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016328:NF-kappa B / Q000276:immunology*; D011494:Protein Kinases / Q000276:immunology; D021381:Protein Transport / Q000276:immunology
chemical_list: D001425:Bacterial Outer Membrane Proteins; D016207:Cytokines; D029968:Escherichia coli Proteins; D016328:NF-kappa B; C078167:OMPA outer membrane proteins; D011494:Protein Kinases