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Visfatin, a Novel Adipocytokine
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B p65 DNA binding in monocytes and increased monocyte and B cell chemotaxis. Mice injected i.p. with murine visfatin had significantly elevated IL-6 plasma levels and high levels of IL-6 mRNA transcripts in their small intestines. Crohn’s disease patients, who have high levels of IL-6 in their intestinal mucosa, had high plasma levels of visfatin. Examination of colonic biopsy specimens from patients with Crohn’s disease or active ulcerative colitis revealed up-regulation of visfatin mRNA compared with healthy tissue. Visfatin protein expression levels were highest in adipocytes, macrophages, and dendritic cells. The authors speculate that obesity-related enhanced visfatin expression results in IL-6 production, insulin resistance, and inflammatory disorders. Evasive Cowpoxvirus
Cowpoxvirus (CPV), a virulent orthopoxvirus, contains immune modulators that can interfere with the adaptive immune response but which are absent from nonvirulent vaccinia virus (VV). It has not been shown that CPV can evade recognition by CTLs. On p. 1654 , Dasgupta et al. showed that CTLs from mice infected with VV or CPV responded to splenocytes from VV-infected, but not CPV-infected, animals. Similar results were obtained using CTLs and monocytes from human PBMCs infected in vitro with VV or CPV; coinfection experiments demonstrated dominance of the CPV immune evasive effect. An early decrease in MHC class I molecule surface levels on CPV-infected human cells compared with uninfected or VV-infected cells was detected by flow cytometry. No changes in intracellular levels of MHC class I molecules were detected by immunoblot analyses or intracellular staining of CPV-infected cells vs controls; however, only CPV-infected cells retained the molecules within the endoplasmic reticulum. Resistance of MHC class I molecules to temperature-dependent degradation in CPV-infected human cells expressing a TAP inhibitor indicated that the virus did not interfere with peptide loading. The authors propose that an unidentified early CPV gene not expressed by VV inhibits intracellular transport of peptide-loaded MHC class I molecules to facilitate CPV evasion of an antiviral T cell response.
Completing the NO Loop
Inducible NO synthase (iNOS) produces NO in LPS-stimulated macrophages. Previous reports from the Kuo laboratory show that NO shuts down its own synthesis by increasing production of osteopontin (OPN), a repressor of iNOS transcription. Following their delineation of the mechanism of OPN up-regulation, Gao et al. (p. 1870 ) examined the OPN-dependent arm of the NO-regulated negative feedback loop. TAP1, OPN, and iNOS expression increased at the protein and mRNA levels in a line of mouse macrophages stimulated with LPS. Transfected OPN short interfering RNA (siRNA) further increased iNOS and TAP1, and eliminated OPN, mRNA expression in the LPS-treated macrophages and stimulated transiently transfected reporter constructs of iNOS and TAP1 promoters. Binding of STAT1 by the iNOS and TAP1 promoters was increased by OPN siRNA in LPS-treated cells. Radioactive pulse-chase experiments showed that a LPS-induced increase in nuclear levels of phosphorylated STAT1 (p-STAT1) were maintained longer in the presence of OPN siRNA; treatment of LPS-stimulated cells with a proteasome inhibitor increased the amount of p-STAT1. The amount of highly ubiquitinated p-STAT1 in LPS-stimulated cells was significantly decreased by OPN siRNA. The above findings were confirmed in primary murine bone marrow-derived macrophages. The ubiquitin enzyme 3 ligase, STAT-interacting LIM (SLIM) protein, coimmunoprecipitated with STAT1 and induced STAT1 degradation in LPS-treated wild-type cells; LPS-treated SLIM–/– cells lacked ubiquitinated STAT1. SLIM was required for STAT1 ubiquitination in an in vitro assay. The data demonstrate that OPN inhibits iNOS gene transcription by increasing degradation of STAT1 ubiquitinated by SLIM.
Vitamin E for Old T Cells
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Preventing Type 1 Diabetes
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-galactosylceramide (GalCer) produce high levels of Th1 and Th2 cytokines that protect NOD mice against T1D, the Lehuen group has shown that iNKT cells act in a cell contact-dependent but cytokine-independent manner. In the first of the two papers, Forestier et al. (p. 1415
) compared fatty acid chain derivatives of GalCer and showed that one (C20:2) induced production of more IL-4 and IL-13 and less IFN-
by mouse iNKT cells in vitro and in sera of injected wild-type and NOD mice than a widely studied analog OCH or several other derivatives. Murine CD1d tetramers bound more strongly to murine iNKT cell TCRs when loaded with C20:2 vs OCH; human CD1d tetramers with C20:2 bound to human iNKT cells and induced Th2 cytokine responses in vitro. NOD mice given seven weekly i.p. injections of C20:2 had delayed T1D, reduced late insulitis, and increased survival compared with controls. A long-lasting decline in the T1D-associated expansion of iNKT cells occurred in spleens and peripheral lymph nodes of C20:2-injected NOD mice compared with vehicle-treated controls; ELISPOT and MHC class I tetramer analyses showed that pancreatic islets of C20:2-injected animals had fewer autoreactive CD8+ T cells. Peripheral lymph node dendritic cells of NOD mice treated with C20:2 did not have the subset alterations and increased expression of maturation markers seen in controls. In the second paper, Novak et al. (p. 1332
) in the Lehuen laboratory looked at the role of peripheral CD1d in T1D inhibition. They found that CD1d+/+ or CD1d–/– iNKT cells inhibited IFN- production by islet peptide-stimulated islet-specific T cells in vitro. Inhibition occurred regardless of the CD1d status of the APCs or T cells or the presence of anti-CD1d mAb. In in vivo experiments, transgenic NOD mice with thymus-specific but no peripheral CD1d expression were fully protected against diabetes induction by injected CD1d–/– islet-specific CD4+ T cells; CD1d–/– controls lacking iNKT cells developed the disease. In a second experiment, only 0.5–0.6% of splenocytes were iNKT in CD1d+/+ or CD1d–/– NOD mice reconstituted with iNKT cells from mice lacking peripheral CD1d expression, yet the animals were protected against diabetes induction by injected CD1d–/– islet-specific CD4+ T cells. Whereas Forestier et al. demonstrate that the GalCer derivative C20:2 induces a strong Th2 cytokine response by activated iNKT cells that protects NOD mice against T1D development, Novak et al. show that the protective effect does not require CD1d expression in the periphery. Understanding Renal I/R
The Holers laboratory reported that ischemia/reperfusion (I/R) of the kidney changes the proximal tubular epithelial cell phenotype from C inhibitory to C activating. However, it is not clear that this change results in production of chemokines that initiate the systemic inflammatory response. Thurman et al. (p. 1819
) in the same laboratory detected increased MIP-2 and keratinocyte-derived chemokine (KC) protein and mRNA expression by gene array analyses on cDNAs from I/R kidneys of wild-type mice but not of mice lacking factor B or of sham-operated controls. Increased mRNA levels for the two chemokines were localized within proximal tubular epithelial cells of kidneys from I/R-treated wild-type mice by in situ hybridization. MIP-2 levels were elevated in sera of wild-type mice after I/R. MIP-2 and KC mRNA levels were increased by exposure of proximal tubular epithelial cells in vitro to serum with an intact alternative pathway; the increase was prevented by selective inhibition of the alternative pathway or by incubation with a C3aR, but not a C5aR, antagonist. A NF-B inhibitor reduced production of MIP-2 and KC by cells in response to serum with an intact alternative pathway. The authors show that the alternative C pathway induces synthesis of two chemokines by proximal tubular epithelial cells in the kidney shortly after I/R. Both C3a and the NF-B pathway are involved in the inflammatory response.
Novel SLE Targets
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Summaries written by Dorothy L. Buchhagen, Ph.D.
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