Journal of interferon research最新文献

Recently, we have shown that in acutely infected T cells interferons (IFNs) effectively inhibit the human immunodeficiency type 1 (HIV-1) proviral DNA synthesis during a single replication cycle. In the present study, we have evaluated the relative effectiveness of IFNs in restricting HIV-1 expression at post-transcriptional level. Treatment of HeLa cells with IFNs A* and B (up to 1,000 U/ml) did not result in a reduction in HIV-1 RNA and protein synthesis encoded by the transfected HIV-1 proviral clone. Interestingly, IFN treatment reduced significantly the HIV-1 mRNA levels encoded by the transfected tat-defective HIV-1 provirus, and this inhibition could be overcome by transfection with Tat- and Rev-expressing plasmids. These results suggest that HIV-1-encoded Tat and Rev can overcome the inhibitory effects of IFNs on HIV-1 replication.

Interferon-alpha/beta (IFN-alpha/beta) suppresses cell cycle activation by platelet-derived growth factor (PDGF) as well as the induction of the 31-kD (pI) and the 35-kD (pII) proteins in density-arrested BALB/c-3T3 cells. We report that elevation of [Ca2+]i by ionomycin induces the synthesis of the 31-kD protein, but not that of the 35-kD protein. Since IFN blocks the PDGF-induced elevation of [Ca2+]i, these results suggest that IFN treatment may suppress pI induction by impairing this PDGF-activated signal transduction pathway. In contrast, because ionomycin did not induce the 35-kD protein, the suppression by IFN of PDGF-induced pII appears to be mediated via a pathway distinct from that operating in the suppression of pI. In BALB/c-3T3 cells, IFN-alpha/beta did not itself affect the turnover or de novo synthesis of inositol phospholipids and the cellular content of diacylglycerol, nor did IFN block the enhancement of these parameters by PDGF.

The in vivo interferon (IFN) activation in Crohn's disease was evaluated by measuring the relative amounts of IFN-alpha and -gamma mRNA in freshly isolated human lamina propria mononuclear cells (LPMC) from patients with Crohn's disease and controls. Both IFN-gamma and IFN-alpha mRNA, as estimated by dot blot analysis, were increased in Crohn's disease (LPMC), although the relative amounts of IFN mRNA appeared to differ among patients. Appreciable amounts of IFN-gamma mRNA were found in Crohn's disease peripheral blood mononuclear cells (PBMC) extracts, whereas the same cells were negative for IFN-alpha mRNA. Only minute amounts of IFN-gamma RNA were found sporadically in control LPMC while no IFN-alpha was detected. Control PBMC were shown to be virtually negative for both IFN-alpha and IFN-gamma mRNA. These data suggest that IFN induction in the normal human gut is a well-controlled function and that in Crohn's disease tissues, both IFN-gamma and IFN-alpha production are dysregulated. The increased IFN activity may represent a major feature in the induction and perpetuation of the chronic inflammatory process in Crohn's disease.

We reported previously that interferon-alpha/beta (IFN-alpha/beta)-treated hepatocytes in culture released a soluble factor(s) that suppressed the multiplication of an INF-alpha/beta-resistant clone of Friend leukemia cells (FLCs). To characterize the factor(s) further, we first examined the possibility that products of nonparenchymal cells (NPCs) included in small number in the hepatocyte cultures were involved in the inhibitory activity. We prepared cultures of purified adherent NPCs, mostly Kupffer cells, and sinusoidal endothelial cells, and culture supernatants of NPCs pretreated with IFN-alpha/beta were tested for the inhibitory activity for FLC multiplication. IFN did not induce any inhibitory activity in NPC cultures, whereas LPS-stimulated NPCs cultivated in parallel released several inhibitory factors including tumor necrosis factor-alpha (TNF-alpha). To explore the possibility that IFN augmented the release of hepatocyte cytosolic proteins, including arginase, we compared the inhibitory activity in culture supernatant of IFN-treated hepatocytes with that found in hepatocyte extract by anion-exchange chromatography. The IFN-induced inhibitory activity was eluted at relatively high salt concentration as a single peak, while the inhibitory activity in hepatocyte extract was co-eluted with arginase at low salt concentration. These results suggested that IFN induced production by hepatocytes of an inhibitor of FLC multiplication.

The expression of mRNAs encoding interferons (IFNs) and IFN-inducible proteins has been studied in psoriatic lesions and in noninvolved skin. The specific mRNAs have been detected by in situ hybridization using antisense RNAs. Signals for the expression of IFN-gamma mRNA have been found exclusively in cells of psoriatic lesions, and most likely represent a subpopulation of infiltrating leukocytes. Weak signals of IFN-alpha mRNA have been detected throughout the hyperkeratotic epidermis, although specific signals for IFN-beta mRNA expression were not detectable. The expression of two IFN-alpha-inducible gene products, namely the MxA protein and the 2'-5' oligoadenylate (2-5A) synthetase, have been studied as markers for the local activation of the IFN-alpha system. Expression of MxA mRNA and protein was observed in psoriatic keratinocytes, but not in normal appearing keratinocytes adjacent to the lesions. Similarly, 2-5A synthetase expression was markedly elevated in psoriatic keratinocytes. The results of the present study indicate that the IFN-alpha system is selectively activated in psoriatic lesions, although it remains silent in noninvolved skin. The implications of this finding are discussed within the boundaries of current understanding of the cytokine network.