Systemic lupus erythematosus (SLE) is associated with the presence of complement proteins and immune complexes in affected organs. Since complement proteins are synthesized in hepatic and extrahepatic sites, we studied a murine model of SLE to ascertain the relative importance of local and humoral (liver) synthesis of complement. C3, C4, and C2 mRNA increase in kidney coincident with the development of nephritis in the MRL lpr/lpr mouse, a strain that spontaneously develops SLE. Two factor B messenger RNA transcripts are expressed in kidney and intestine; SLE nephritis is associated with decrease in the long factor B mKNA and increase in the short form. Increased local synthesis of C3 and I1 protein and a concomitant glomerular and renal interstitial macrophage infiltrate paralleled the increase in mRNA content in the (lpr/ lpr) mice. In addition to kidney, an increase in C3, C4, C2 and factor B mRNA was noted in the lung, heart and intestine and to a lesser extent in liver of (Ipr/lpr) in comparison to the MRL (+/+) animals.These results suggest that in SLE local expression of complement genes plays a role in the pathogenesis of chronic glomerulonephritis and in the autoimmune arteritis of other organs.
Low-dose X-irradiation between 0.3 and 0.7 Gy induced a relative maximum of TGF-beta(1) production by stimulated EC. This results in a down-regulation of leukocyte/PBMC adhesion and may contribute to the anti-inflammatory effect of LD-RT.
The ability of the enteropathogenic Yersinia enterocolitica to survive and proliferate in host tissue depends on a 70-kb plasmid known to encode a number of released Yersinia outer proteins that act as virulence factors by inducing cytotoxicity and inhibiting phagocytosis. This study demonstrates that one of the Yersinia outer proteins, the 41-kDa YopB, suppresses the production of tumor necrosis factor alpha (TNF-␣), a macrophagederived cytokine with central roles in the regulation of immune and inflammatory responses to infection. This conclusion is based on several lines of evidence. First, in macrophage cultures, suppression of TNF-␣ mRNA expression was induced by culture supernatant (CS ؉) of plasmid-bearing yersiniae, the effect which was blocked by anti-YopB antiserum. Second, suppression of TNF-␣ production, but not of interleukin-1 (IL-1) and IL-6, was induced by purified YopB. Third, in Yersinia-infected mice, no increase in TNF-␣ mRNA expression was observed in Peyer's patches, the primary site of bacterial invasion, compared with IL-1 (␣ and ) mRNA. Finally, administration of anti-YopB antiserum to mice prior to infection with Y. enterocolitica increased TNF activity levels in Peyer's patches and coincided with a reduction in bacterial growth. The results thus provide direct evidence for a secreted eubacterial virulence factor that mediates selective suppression of TNF-␣ production. Although suppression of this single cytokine response is probably not sufficient to facilitate survival of the infecting organisms, the results suggest that suppression of TNF-␣ production by YopB significantly contributes to the evasion of Y. enterocolitica from antibacterial host defense.
Macrophage-inflammatory protein 2 (MIP-2) is a major CXC chemokine involved in the migration of polymorphonuclear neutrophils (PMNs) to sites of inflammation. Although cell culture experiments have identified different cell types that can produce MIP-2, the cellular sources in vivo are not clearly defined. By using immunohistochemical staining and analysis of chemokine mRNA expression, the present study aimed to localize cells producing MIP-2 in tissues of normal mice and mice challenged with Yersinia enterocolitica. The results showed a constitutive expression of MIP-2 mRNA in bone marrow (BM) of normal mice, but not in other organs such as spleen, lung, or liver. MIP-2 protein was found in all organs tested but it was exclusively associated with PMNs that stained positive with the cell surface marker Gr-1. Bacterial infection caused a 5-fold increase in the number of MIP-2-positive PMNs recruited to spleens concomitant with a strong increase of splenic MIP-2 mRNA. This correlated well with a 3-fold loss of MIP-2-producing cells in BM. Because MIP-2 mRNA expression in PMNs was increased after stimulation with TNF, the results indicate that newly recruited PMNs can supplement their MIP-2 content through TNF-stimulated transcription. Together, the data imply a constitutive production of MIP-2 by a subset of PMNs in BM and argue for the possibility of a rapid mobilization of MIP-2 through its storage in circulating PMNs.
The lipopeptide N-palmitoyl-S-(2,3-bis(palmitoyloxy)-(2RS)-propyl)-(R)-cysteinyl-a lanyl-glycine (Pam3Cys-Ala-Gly), a synthetic analogue of the N-terminal part of bacterial lipoprotein, induces the secretion of interleukin (IL) 1, IL 6 and tumor necrosis factor (TNF)-alpha in bone marrow-derived macrophages that have been cultured in vitro for up to 20 days. IL 6 and TNF-alpha secretion increased from day 6 to day 20 whereas IL 1 secretion increased until day 13 and decreased on day 20. In contrast to the enhancement of cytokine production, phagocytosis of IgG-coated sheep erythrocytes and Ia expression were found to be diminished after treatment with lipopeptide for 24 h. Morphological studies revealed lipopeptide-induced changes of macrophage cultures. The data presented here show the potential of the lipopeptide as a strong activator of bone marrow-derived macrophages.
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