Role of Toll-like receptor signaling in the apoptotic response of macrophages to Yersinia infection.
Macrophages encode several Toll-like receptors (TLRs) that recognize bacterial components, such as lipoproteins (TLR2) or lipopolysaccharides (TLR4), and activate multiple signaling pathways. Activation of transcription factor NF-kappaB by TLR2 or TLR4 signaling promotes proinflammatory and cell survival responses. Alternatively, TLR2 or TLR4 signaling can promote apoptosis if the activation of NF-kappaB is blocked. The gram-negative bacterial pathogen Yersinia pseudotuberculosis secretes into macrophages a protease (YopJ) that inhibits the activation of NF-kappaB and promotes apoptosis. We show that primary macrophages expressing constitutively active inhibitor kappaB kinase beta (IKKbeta) are completely resistant to YopJ-dependent apoptosis, indicating that YopJ inhibits signaling upstream of IKKbeta. Apoptosis is reduced two- to threefold in TLR4(-/-) macrophages infected with Y. pseudotuberculosis, while the apoptotic response of TLR2(-/-) macrophages to Y. pseudotuberculosis infection is equivalent to that of wild-type macrophages. Therefore, TLR4 is the primary source of apoptotic signaling in Yersinia-infected macrophages. Our results also show that a small percentage of macrophages can die as a result of an apoptotic process that is YopJ dependent but does not require TLR2 or TLR4 signaling.
Zhang
Yue
Y
Center for Infectious Diseases, Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, New York 11794-5120, USA.
Bliska
James B
JB
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000502:physiology; D029721:Drosophila Proteins; D051550:I-kappa B Kinase; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000382:microbiology* / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015011:Yersinia pseudotuberculosis / Q000472:pathogenicity*
D001426:Bacterial Proteins; D029721:Drosophila Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C109227:YopP protein, Yersinia; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse