Role of the ceramide-signaling pathway in cytokine responses to P-fimbriated Escherichia coli.
Escherichia coli express fimbriae-associated adhesins through which they attach to mucosal cells and activate a cytokine response. The receptors for E. coli P fimbriae are the globoseries of glycosphingolipids; Gal alpha 1-->4Gal beta-containing oligosaccharides bound to ceramide in the outer leaflet of the lipid bilayer. The receptors for type 1 fimbriae are mannosylated glycoproteins rather than glycolipids. This study tested the hypothesis that P-fimbriated E. coli elicit a cytokine response through the release of ceramide in the receptor-bearing cell. We used the A498 human kidney cell line, which expressed functional receptors for P and type 1 fimbriae and secreted higher levels of interleukin (IL)-6 when exposed to the fimbriated strains than to isogenic nonfimbriated controls. P-fimbriated E. coli caused the release of ceramide and increased the phosphorylation of ceramide to ceramide 1-phosphate. The IL-6 response to P-fimbriated E. coli was reduced by inhibitors of serine/threonine kinases but not by other protein kinase inhibitors. In contrast, ceramide levels were not influenced by type 1-fimbriated E. coli, and the IL-6 response was insensitive to the serine/threonine kinase inhibitors. These results demonstrate that the ceramide-signaling pathway is activated by P-fimbriated E. coli, and that the receptor specificity of the P fimbriae influences this process. We propose that this activation pathway contributes to the cytokine induction by P-fimbriated E. coli in epithelial cells.
Hedlund
M
M
Department of Medical Microbiology, University of Lund, Sweden.
Svensson
M
M
Nilsson
A
A
Duan
R D
RD
Svanborg
C
C
D000818:Animals; D001422:Bacterial Adhesion; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002460:Cell Line; D002518:Ceramides / Q000737:chemistry / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium; D004926:Escherichia coli / Q000235:genetics / Q000502:physiology*; D010861:Fimbriae, Bacterial / Q000502:physiology*; D005838:Genotype; D006028:Glycosphingolipids / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006384:Hemagglutination; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D007680:Kidney Neoplasms; D008969:Molecular Sequence Data; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D002518:Ceramides; D016207:Cytokines; D004791:Enzyme Inhibitors; D006028:Glycosphingolipids; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases