Salmonella typhimurium SH5014 porins induce the release of tumor necrosis factor alpha (TNF-), interleukin lee (IL-la), and IL-6 by human monocytes and of gamma interferon (IFN-y) and ILH4 by human lymphocytes. Porins at 1 ,ug/ml induce the greatest release of TNF-a, IL-let, and IL-6 by monocytes and of I]LA by lymphocytes, while porins at 5 ,ug/ml induce the greatest release of IFN-y by lymphocytes. The R form of lipopolysaccharide (LPS-R) induces the greatest release of TNF-a and IL-lee by monocytes when used at a low concentration (1 jLg/mI). At higher concentrations (5 and 10 ,ug/ml, respectively), LPS-R induces the maximal release of IL-6 from monocytes and the maximal release of IL-4 from lymphocytes. The S form of LPS (LPS-S) induces the greatest release of TNF-e, IL-le, and IL-6 by monocytes and that of IL-4 by lymphocytes when used at a concentration of 1 ;ag/ml. After stimulation with LPS-S, the largest quantity of TNF-a and IL-let released was less than that obtained after stimulation with LPS-R at the same concentration, while the quantity of IL-6 released was found to be slightly higher than that obtained after stimulation with porins or LPS-R. LPS-S (1 ,ug/ml) induces IFN-y release from lymphocytes in notably smaller quantities than that obtained with LPS-R and slightly larger quantities than that obtained with porins. The preparation of porins used was found to be contaminated with 10 pg of LPS per 10 jLg of porins, a quantity which was found to have no biological effect; furthermore, porin preparations with the addition of polymyxin B gave the same results. Many of the pathophysiologic mechanisms of gram-negative bacterial infections are due to endotoxins acting on tissue directly or via mediators such as cytokines (40). Mediators of these reactions include tumor necrosis factor (TNF), interleukin la (IL-la), and IL-6 (2, 8, 9) released by monocytes. In addition, endotoxins appear to potentiate antigen-specific proliferation of T helper cell lines (4); among the different mediators released by lymphocytes, IL-4 and gamma interferon (IFN-y) are of particular interest. There

Seminal vesicle protein IV (SV-IV) is a secretory anti-inflammatory, procoagulant, and immunomodulatory protein produced in large amounts by the seminal vesicle epithelium of the rat under the strict transcriptional control of androgen. In particular, this protein was shown to possess the ability to markedly inhibit in vivo the humoral and cell-mediated immune responses of mice to nonbacterial cellular antigens (sheep erythrocytes and spermatozoa). We report data that demonstrate that in mice treated with SV-IV and infected with Salmonella enterica serovar Typhimurium, SV-IV is able to downregulate some important immunological and biochemical parameters that serovar Typhimurium normally upregulates in these animals. This event did not correlate with a lower bacterial burden but was associated with a markedly increased one (300%). Furthermore, the treatment of mice with SV-IV alone also produced a significant increase in the rate of mortality among serovar Typhimurium-infected animals. The mechanism underlying these phenomena was investigated, and the strong immunosuppression produced by SV-IV in serovar Typhimurium-infected mice was suggested to be the basis for the increased rate of mortality. The SV-IV-mediated immunosuppression was characterized by a decrease in the humoral and cell-mediated immune responses, altered lymphocyte-macrophage interaction, downregulation of cytokine and inducible nitric oxide synthase gene expression, inhibition of macrophage phagocytosis and intracellular killing activities, and absence of apoptosis in the splenocyte population of SV-IV-and serovar Typhimurium-treated mice. The immunosuppressive activity of SV-IV was specific and was not due to aspecific cytotoxic effects. SV-IV-specific receptors (K d ‫؍‬ 10 ؊8 M) occurring on the macrophage and lymphocyte plasma membranes may be involved in the molecular mechanism underlying the SV-IV-mediated immunosuppression. Some results obtained by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay also revealed a functional impairment of mitochondria (a decrease in mitochondrial dehydrogenase activity), thus indicating the possible implication of these organelles in the immunosuppressive process.

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