Suppression of in vitro growth of virulent and avirulent herpes simplex viruses by cell-mediated immune mechanisms, antibody, and interferon.

A rounding cell-forming--GC strain, which is a variant of a syncytial giant cell-forming herpes simplex virus (+GC Miyama strain), was highly attenuated for Swiss, BALB/c nu/nu, and nu/+ mice, whereas +GC was highly virulent to all the mice tested. +GC and -GC were antigenically indistinguishable from each other by cross-neutralization and cross-immunization. Immunosuppression induced by cyclophosphamide converted the nonlethal -GC infection of mice into a fatal infection. -GC replication in tissue culture was more effectively suppressed by spleen cells immunized with either +GC or -GC than was the +GC replication. -GC replication was also inhibited more effectively by antibody or the antibody-dependent cell-mediated system than was the +GC replication. -GC is highly sensitive to mouse interferon, but +GC was relatively resistant. These findings indicate that attenuation of this avirulent -GC strain may be due to a high susceptibility of its replication to humoral and cell-mediated defense factors. The probable roles of each defense factor in recovery from the infection with virulent and attenuated herpes simplex virus are also discussed.     

Heat shock protein 60 (HSP60) immunoreactivity in gastric epithelium associated with Helicobacter pylori infection: a pitfall in immunohistochemically interpreting HSP60-mediated autoimmune responses

Previous studies have suggested that heat shock proteins (HSP) of Helicobacter pylori (H. pylori) are involved in the induction of autoimmunity mediated gastritis. In the present report, the cross-reactivity between H. pylori-related HSP60 and gastric epithelial cells was investigated by the indirect immunoperoxidase method using two monoclonal antibodies (mAb) against H. pylori-derived HSP60, H9 and H20. H9 is reactive with an epitope common to bacterial HSP60, while H20 is specific to H. pylori HSP60. A total of 70 paraffin-embedded gastric biopsy specimens were analyzed after heat-induced epitope retrieval. Both mAb were cross-reactive with the gastric epithelial cells, with a higher frequency seen for the H9-reactive epitope. The frequency of positive epithelial decoration was not significantly different between H. pylori-positive and H. pylori-negative gastric mucosae. A variety of epithelial and non-epithelial cells were immunostained with mAb H9, while mAb H20 was cross-reactive only with small intestinal epithelia. Reactivity was mainly located in the Golgi area and rarely in the cytoplasm. These results suggest a noteworthy pitfall in immunohistochemical interpretations of HSP60-associated autoimmune reactions in the gastric mucosa.     

Presynaptic opioid kappa-receptor and regulation of the release of Met-enkephalin in the rat brainstem

Opioid kappa-agonists had much more potent inhibitory effects on the high K+-evoked Met-enkephalin release from rat brain slices than did the mu- or delta-agonists. The opioid kappa- antagonist, MR2266 enhanced the evoked release of Met-enkephalin to a greater extent than did mu- or delta-antagonists in vitro and had a potent analgesia in mice in vivo. These findings suggest that the release of Met-enkephalin may be regulated in vitro and in vivo, mainly by presynaptic kappa-receptor-mediated mechanisms.     

Acetaminophen-induced immunosuppression associated with hepatotoxicity in mice

We investigated the influence of acetaminophen (APAP), an analgesic and hepatotoxic agent, on the immune system in mice. The activity of serum glutamic-pyruvic transaminase was markedly increased by about 200 fold compared to that of the vehicle control following intraperitoneal injection of 400 mg/kg of APAP. In vivo antibody-producing responses to SRBC was significantly inhibited by APAP in a dose-dependent manner, while in vivo T cell-independent antibody-producing responses to TNP-Ficoll was not inhibited. The addition of thymocytes from APAP-treated mice suppressed the response to SRBC in vitro. Thymocyte blastogenesis following mitogenic stimulation with concanavalin A was also inhibited by injection of APAP. The delayed-type hypersensitivity response and mixed lymphocyte reaction, which are used to evaluate cell-mediated immunity, were also significantly reduced after treatment with APAP. These results indicate that APAP suppresses the humoral and cell-mediated immune responses at a dose that causes liver injury.     

The 3111T/C polymorphism of hClock is associated with evening preference and delayed sleep timing in a Japanese population sample.

Sleep timing is influenced by the circadian system. Morningness-eveningness (ME) preference in humans is affected by the free-running period, which is determined by circadian clock-relevant genes. In this study, we investigated association between the 3111T/C polymorphism in the 3'-flanking region of hClock (Homo sapiens Clock homolog) and ME preference in 421 Japanese subjects. The Horne-Ostberg ME questionnaire (MEQ) scores showed normal distribution, with mean score of 51.2 +/- 1.4 (range, 25-73), and scores were positively correlated with sleep onset time (r = 0.541, P < 0.001) and wake time (r = 0.513, P < 0.001). MEQ scores were significantly lower in subjects with 3111C/C (n = 12) than in subjects with 3111T/C (n = 106, P < 0.001) or 3111T/T (n = 303, P < 0.001), suggesting a stronger eveningness preference in 3111C/C homozygotes. This group also showed significantly delayed sleep onset (P < 0.001), shorter sleep time (P < 0.001), and greater daytime sleepiness (P < 0.001) in comparison to parameters in the subjects with the 3111T allele. There was no significant difference in any of these parameters between the 3111C/T and 3111T/T genotypes. The influence of the 3111T/C polymorphism on ME preferences in Caucasian populations remains controversial. The present findings in a Japanese population sample, which should have a relatively low risk of population stratification effects, suggest the significance of the association of the 3111C/C allele of hClock with evening preference.     

Neonatal impact of leukemia inhibitory factor on neurobehavioral development in rats

Cytokines have been implicated in the etiology or pathology of various psychiatric diseases of developmental origin such as autism and schizophrenia. Leukemia inhibitory factor (LIF) is induced by a variety of brain insults and known to have many influences on mature and immature nervous system. Here, we assessed the neurobehavioral and pathological consequences of peripheral administration of LIF in newborn rats. Subcutaneous LIF injection induced STAT3 phosphorylation in many brain regions and increased glial fibrillary acidic protein (GFAP) immunoreactivity in the neocortex, suggesting that LIF had direct effects in the central nervous system. The LIF-treated rats displayed decreased motor activity during juvenile stages, and developed abnormal prepulse inhibition in the acoustic startle test during and after adolescence. They displayed normal learning ability in active avoidance test, however. Brain neuronal structures and startle responses were grossly normal, except for the cortical astrogliosis during neonatal LIF administration. These results indicate that LIF induction in the periphery of the infant has a significant, but discrete impact on neurobehavioral development.