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NF-
B in Bacteria-Induced Colitis
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BEGFP (EGFP, epidermal growth factor protein) mouse under germfree conditions to look at NF-B activation in the small intestine after colonization with commensal bacteria Escherichia faecalis plus Escherichia coli. EGFP expression (NF-B activation) limited to the colonic epithelium was observed at 1-wk postinfection in both strains by confocal microscopy. At 7-wk postinfection, IL-10–/– NF-BEGFP, but not NF-BEGFP, mice exhibited distal colon inflammation with EGFP+ dendritic and T cells containing phosphorylated NF-B RelA in the lamina propria mononuclear (interstitial) cells. Bone marrow-derived dendritic cells (BMDCs) from IL-10–/– transgenic animals rapidly phosphorylated RelA and IB
and produced higher levels of IL-23 than wild-type or IL-10–/– cells after bacterial stimulation in vitro; an NF-B inhibitor blocked IL-23 production in BMDCs. IB degradation and IL-23 mRNA expression did not occur in bacteria-stimulated IL-10–/–MyD88–/– BMDCs. Treatment of bacteria-colonized IL-10–/– NF-BEGFP mice for 5 wk with the NF-B inhibitor reduced colitis, lowered colonic expression of EGFP, and decreased production of IL-23 compared with controls. The authors provide evidence that bacteria-induced colitis involves TLR-mediated NF-B activation in the lamina propria in the IL-10–/– mouse model of inflammatory bowel disease. I Don’t Recognize You
Recognition of microbial components as an initial response of the innate immune system is mediated by TLRs. The Tapping laboratory showed that a leucine-rich region of human TLR1 is required for recognition of bacterial lipopeptides. In an extension of their work, Omueti et al. (p. 6374 ) used site-directed mutagenesis to introduce three naturally occurring TLR1 single nucleotide polymorphisms (SNPs) into TLR1 at a region of leucine-rich repeats; human cells were transfected with vectors expressing the mutants. One SNP-containing TLR, in which a leucine replaced a proline at position 315, failed to bind an anti-TLR1 mAb. Exposure of the same transfected cell line (cotransfected with TLR2) to synthetic or natural lipopeptides failed to induce an intracellular IL-8-driven luciferase gene. Five mutants with different amino acid substitutions at proline 315 had attenuated responses to lipopeptide agents, with the leucine and arginine mutants being the most impaired. A coexpressed CD14 coreceptor was unable to rescue the activity of any mutant. The anti-TLR1 mAb reduced activity of wild-type TLR1-transfected cells toward lipopeptides but had no effect on activity of cells expressing the leucine or arginine mutant. The authors propose that proline 315 is critical for TLR1 recognition of microbial lipopeptides and that the 315 leucine mutation might impact disease susceptibility in humans.
LPS to T Cells: Don’t Die
Survival of activated T cells is enhanced by their exposure to LPS within 24 h of treatment with staphylococcal enterotoxin A (SEA), but the mechanism for the LPS effect is not known. Following up on reports that the proapoptotic serine/threonine kinase, glycogen synthase kinase-3
(GSK-3), is inactivated in stimulated T cells, Sengupta et al. (p. 6073
) found increased survival of SEA-stimulated mouse T cells treated with GSK-3 inhibitors ex vivo; no further increase in survival was seen for T cells from mice treated with SEA plus LPS. The inhibitor also increased the ex vivo survival of T cells from OVA peptide-injected mice adoptively transferred with OVA-TCR transgenic T cells, and no further increase was seen for T cells from mice injected with OVA plus LPS. Activated T cells survived longer in mice treated with the inhibitor 7 days after SEA injection compared with controls not injected with inhibitor. Increased in vivo survival of in vivo-activated T cells was achieved by transfecting them with a retrovirus expressing a dominant-negative GSK-3 before adoptive transfer. Elevated expression of two cell survival proteins was detected by immunoblot analysis of extracts of inhibitor-treated T cells from OVA TCR transgenic mice injected with OVA peptide or of T cells from transgenic mice injected with OVA peptide plus LPS. LPS increased the stability of the phosphorylation-inhibited form of GSK-3 that appeared in T cells after injection of mice with SEA. The authors demonstrate that inhibition of GSK-3 by LPS, chemicals, or a dominant-negative GSK-3 prevents activated T cell death in vivo and ex vivo.
Angiogenesis in Asthma
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Helicases Regulate Viral Resistance
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and IFN-2 mRNA and protein, other dsRNA-inducible genes, and NF-B activity in poly(I:C)-treated primary mouse embryo Lgp2–/– fibroblasts compared with wild-type cells. In contrast, no differences in cytokine levels were detected between wild-type and Lgp2–/– mice inoculated with poly(I:C). Additional increases of IFN- and IFN-2 mRNA production by poly(I:C) were seen in mutant cells transfected with vectors expressing MDA5 or RIG-1 vs control cells; production declined rapidly between 6 and 12 h poststimulation. Infection of Lgp2–/– macrophages with either a negative- or a positive-stranded virus resulted in slightly elevated production of mRNAs for both IFNs and reduced viral replication. Mutant mice inoculated intranasally with either virus were resistant to infection, but wild-type control mice died. High titers of virus were recovered from brains of only wild-type mice, and replication of luciferase-tagged virus was greater in the nasal region of wild-type mice at 7 days postinfection. Levels of inflammatory mediators in sera were slightly higher in infected wild-type mice, and IFNs were detected in brain extracts of only infected wild-type animals. Mutant mice infected with virus had early high IFN- and IFN-
serum levels. The data indicate that Lgp2 dampens the innate immune response to virus infection by negatively regulating the ability of RIG-I and MDA5 to induce type I IFN. CD4+ T Cell Innate Responsiveness
The ability of Ag-experienced effector CD8+ T cells to respond to Ag-specific stimuli by producing IFN- is well documented. Although the McSorley laboratory found large numbers of activated CD4+ T cells in mice infected with Salmonella typhimurium and injected with heat-killed S. typhimurium (HKST) that produced IFN- ex vivo, there is no evidence that the cells can respond to innate triggering. Srinivasan et al. (p. 6332
) in the McSorley laboratory measured rapid ex vivo production of IFN- and TNF- by CD4+ T cells from infected but not naive animals injected with HKST; injection with ultrapure LPS induced only IFN-. Cytokine production induced by HKST or LPS was greatest at the peak of bacterial infection (14 days postinfection (p.i.)), was diminished for both agents at bacterial clearance (40 days p.i.), and was low in response to HKST and absent to LPS at 3 mo p.i. CD4+ and CD8+ T cells from HKST-injected mice infected with Listeria monocytogenes also produced IFN- but not TNF-. CD4+ T cells from HKST- or LPS-injected wild-type or MHC class II–/– mice adoptively transferred with congenic CD4+ T cells from S. typhimurium-infected animals produced IFN- but not TNF-. HKST injection of S. typhimurium-infected IL-18–/– or IL-18R–/– mice stimulated ex vivo production of both cytokines by CD4+ T cells that was reduced at 13 days p.i. and lost at 45 days p.i. compared with wild-type controls; bacterial counts were higher in IL-18–/– mice at every stage of infection. The data indicate innate responsiveness of CD4+ T cells in S. typhimurium infected-mice that is dependent on IL-18 and independent of MHC class II and Ag.
A Polarized Pulmonary Response
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, IFN-, or IL-4 to the basolateral, but not the apical, surface induced STAT phosphorylation. Similarly, basolateral application of TNF- induced release of IL-8 from both surfaces and activated a transfected luciferase-NF-B expression vector; Hemophilus influenzae applied to either surface activated NF-B. Correspondingly, the IFN-R and IL-4R were found basolaterally on the cultured cells and on normal human airway tissue by immunofluorescence and immunoblot analysis. STAT phosphorylation followed application of IFN- or other mediators to either side of cultured epithelial cells injured mechanically or treated with anti-E-cadherin Ab; injury enhanced the response to basolateral application of H. influenzae. Lungs from mice given IFN- in conjunction with a compound that damaged their airways also had phosphorylated STAT, whereas none was detected in lungs from control animals. The authors propose that this polarized pulmonary response preserves pulmonary function by modulating the immune response to match the degree of injury from infecting microbial pathogens or from environmental insults. Summaries written by Dorothy L. Buchhagen, Ph.D.
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B Pathway
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