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Modulation of Toll-like receptor 2 signaling by soluble TLR2
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than in the absence of sTLR2. High levels of sTLR2 polypeptides were detected in postpartum human breast milk by immunoblot analyses; these levels were equivalent to levels of sCD14, the TLR2 coreceptor that coprecipitated with sTLR2 from the same sample. The authors propose that sTLR2 interacts with sCD14 to modulate TLR2 signaling and that sTLR2 can be useful in preventing or in treating septic shock.
PPAR
ligands and sepsis
Peroxisome proliferator activated receptor- (PPAR) is a member of the nuclear subfamily of transcription factors. While it is known to act in metabolic homeostasis, its role in septic shock has not been determined. Zingarelli et al. (p. 6827
) used a rat model of cecal ligation and puncture (CLP) to study the effect of two PPAR ligands, 15-deoxy-
12,14-PGJ2 (15d-PGJ2) and ciglitazone, on sepsis. After CLP, rats treated with 15d-PGJ2 and ciglitazone had survival rates of 82% and 65% at 96 h compared with 50% for vehicle-treated animals. There were no significant differences in bacterial counts or blood glucose levels between the ligand-treated and vehicle-treated rats; blood pressure improved only in the ligand-treated animals. The decreased expression of PPAR protein in the lungs and aortas of vehicle-treated rats was reversed by in vivo treatment with 15d-PGJ2 and, to a partial extent, with ciglitazone. Nitrotyrosine formation and neutrophil infiltration in lung tissues of CLP rats was reduced by treatment with the ligands. Similarly, the ligands reduced the levels of cytokines (TNF-, IL-2, and IL-10), decreased the early activation and DNA binding of NF-
B and AP-1, inhibited the degradation of IB, and reduced IB kinase complex and c-Jun-NH2-terminal kinase activation after CLP compared with vehicle-treated animals. These findings suggest that PPAR ligands may have applicability in the clinical treatment of sepsis and may lead to increased survival.
Virus-induced autoimmune diabetes
Viral infections can cause inflammation and autoimmune diseases. Inflammation is mediated by chemokines attempting to eliminate intracellular virus. The mechanism by which autoimmune disease develops is less clear. Christen et al. (p. 6838
) studied chemokine production following acute lymphocytic choriomeningitis virus (LCMV) infection of transgenic mice expressing the LCMV glycoprotein under control of the rat insulin promoter (RIP) in the 
-cells of the islets of Langerhans (RIP-GP mice). One day following LCMV infection, expression of the CXCR3 chemokine, IP-10, was increased >400-fold in the pancreata of wild-type and RIP-GP mice compared with uninfected controls. A second CXCR3 chemokine, Mig (monokine induced by IFN-), had a 30-fold increased expression between 2 and 7 days after LCMV infection. The incidence of diabetes in wild-type and RIP-GP mice was reduced 31% by i.p. injection of anti-IP-10 Ab, but not anti-Mig Ab, compared with saline- or IgG-injected LCMV-infected mice. The -cells in infected mice treated with the anti-IP-10 Ab retained normal morphology and insulin production, whereas those in untreated, infected mice lost the ability to produce insulin and were destroyed within 23 days postinfection by infiltrating CD8+ T cells. Fluorescence-tagged T cells transgenic for a specific LCMV-GP epitope injected into LCMV-infected mice localized in the spleen, blood, and pancreas. The numbers of injected cells at each of these sites was reduced by anti-IP-10 Ab treatment. Other pancreas-tropic viruses, but not viruses that are nontropic for the pancreas, induced elevated IP-10 levels. The data show that enhanced IP-10 expression induces autoimmune diabetes and that the disease can be blocked by anti-IP-10 Ab.
Soluble decoy ligands in tumor evasion
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T cells surviving hypoxia
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, one component of the complex, was expressed in the cytoplasm of human CD3+ T cells from a rheumatoid arthritis inflamed joint. Hypoxia (1% O2) reduced the massive activation-induced cell death (AICD) seen for PHA-activated human peripheral blood T cells incubated with IL-2 and anti-CD3 mAb under normoxic (21% O2) conditions. Increased survival was evident at O2 concentrations of 5–7%. HIF-1 protein was detected only in cells under hypoxic conditions (below 7% O2). Gene expression profiling experiments revealed that adrenomedullin (AM) was highly expressed in T cells in response to CD3 stimulation under hypoxic conditions. Jurkat T cells transiently transfected with a constitutively active HIF-1 reporter gene had enhanced expression of AM and decreased AICD compared with parent Jurkat cells. Moreover, the resistance of the transfected cells to AICD was lost when the AM receptor was blocked by specific peptides. The authors conclude that sequential expression of HIF-1 and AM is critical to survival of activated T cells in a hypoxic milieu. Islet allograft survival
Widespread use of pancreatic islet allografts as therapy for patients with type I diabetes is limited by graft rejection. The involvement of chemokine/chemokine receptor pathways in rejection of islet allografts has not been clarified. Lee et al. (p. 6929
) found high levels of monocyte chemotactic protein-1 (MCP-1) mRNA in murine islets seven days after engraftment into diabetic allogeneic mice compared with isograft controls. At the same time, high mRNA levels of the MCP-1 receptor, CCR2, were detected in mononuclear cells of the allogeneic recipients. CCR2-/- mice treated with a low dose of the immunosuppressant rapamycin, and wild-type mice treated with a combination of anti-MCP-1 mAb and rapamycin, permanently retained allogeneic islet grafts. Rapamycin- or IgG-treated wild-type mice and untreated CCR2-/- mice rejected their grafts by 20 days. Activation of both CD4+ and CD8+ T cells and production of IL-2 and IFN- were reduced in CCR2-/- and MCP-1-/- mice compared with wild-type controls; rapamycin further attenuated these responses. Leukocytes infiltrating islet allografts in wild-type recipients treated with anti-MCP-1 mAb plus rapamycin expressed high levels of programmed death-1 (PD-1) and its ligand PD-L1. Inclusion of anti-PD-L1 mAb from the time of engraftment in these animals led to islet rejection by 20–25 days. The data show that targeting MCP-1 or CCR2 in conjunction with rapamycin prevented islet graft destruction in this model system and demonstrate the importance of the PD-1 pathway in long-term graft survival.
Beyond 12/23 recombination
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locus. Hughes et al. (p. 6604
) determined the requirements for components of the 5' D RS in enforcing the B12/23 restriction. Chimeric mice were generated by recombinase activating gene-deficient blastocyst complementation using four independent ES cell lines transfected with a TCR minilocus containing one V, one D, and two J gene segments linked to an enhancer and constant region gene. V to DJ rearrangement of the minilocus during thymocyte development was blocked in chimeric mice carrying miniloci with 5' D 12RS heptamer/nonamer sequence mutations. Analyses of additional minilocus mutations showed that the nonamer sequence and the D RS spacer were essential for enforcing the B12/23 restriction. Transcript initiation from the D 12RS was not required. The 5'D 12RS nonamer and spacer sequences also were required for rearrangement of similar extrachromosomal recombination substrates in nonlymphoid cell lines. The authors conclude that functional synaptic complexes require conservation of a single RS within a functional RS pair. Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
Ligands, 15-Deoxy-12,14-Prostaglandin J2 and Ciglitazone, Reduce Systemic Inflammation in Polymicrobial Sepsis by Modulation of Signal Transduction Pathways
-Inducible Protein of 10 kDa (CXC Chemokine Ligand (CXCL) 10) but Not Monokine Induced by IFN- (CXCL9) Imprints a Pattern for the Subsequent Development of Autoimmune Disease
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