Effect of Protein SV-IV on ExperimentalSalmonella entericaSerovar Typhimurium Infection in Mice

Abstract

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.

Anti-apoptotic seminal vesicle protein IV inhibits cell-mediated immunity

“…2).These data are consistent with similar binding observations already published (Metafora et al, 1989;Morelli et al, 2007). (Stiuso et al, 1999;Romano-Carratelli et al, 2002). The binding at 37°C was found about 25% lower, probably as consequence of a slight release of counts from cell surface caused by the relatively high Kd.…”

Antiapoptotic Seminal Vesicle Protein IV Induces Histamine Release from Human FcεRI+ Cells

“…These results: (a) are in line with the antiapoptotic and immunosuppressive properties of SV-IV [13,17,19,20,21,22,23,24,28]; (b) confirm a modulatory activity of this protein on mammal inflammation reactivity by either inhibiting the arachidonate cascade pathway [19,21] or stimulating the release of proinflammatory cytokines from lymphocytes/monocytes [13] and histamine from FcεRI+ cells; (c) raise the possibility of a protective role of SV-IV on implanting hemiallogenic blastocyst against reactive oxygen species and maternal immunological attacks at the uterine implantation site in concert with other local immunosuppressive cells (mast cells and CD4+CD25+ FoxP3+ regulatory T cells), cytokines (TGF-β 1 , IL-10), and antiapoptotic factors (leukemia inhibitory factor, heme oxygenase 1, peroxidases and histamine).…”

“…SV-IV exerts a non-species-specific inhibitory activity on inflammation, cell-mediated and humoral immunity, and apoptosis [13,17,18,19,20,21,22,23,24,25]. In addition, it possesses a stimulatory effect on purified peroxidases [25,26] and protects cells against oxidative-stress-induced damage, by acting as an indirect reactive-oxygen-species scavenger [25].…”

“…Besides, SV-IV immunosuppressive properties suggest a defensive role against maternal immunological attack of hemiallogenic implanting blastocysts [11,19,23,25,27]. The anti-inflammatory effect of the protein is related to phospholipase A 2 (PLA 2 ) inhibition, while its immunomodulatory activity is generated by interference with macrophage-T cell cooperation (modulation of cytokine production; inhibition of macrophage antigen presentation and T cell activation) [13,19,20,21,22,23,24,28]. …”

Conformational Analysis of Rat Seminal Vesicle Secretory Protein 4, an Intrinsically Disordered Protein Having Interesting Pharmacological Properties

“…RSV4 was obtained from the seminal vesicle secretion of adult rats (Fisher-Wistar) according to our previous protocols and subjected to further purification using an FPLC system by ion exchange chromatography to obtain protein samples rich of the monomer with a low time-dependent contamination of dimeric/trimeric forms (Romano-Carratelli et al, 2002). The samples were immediately used for far UV CD measurements to obtain far UV spectra best of those obtained in the past (Caporale et al, 2004) with better resolution.…”