No abstract

Oligodendrocytes (OLGs) produce and maintain myelin in the central nervous system (CNS). In the demyelinating autoimmune disease multiple sclerosis, OLGs are damaged and those remaining fail to fully remyelinate CNS lesions. Therefore, current therapies directed to restrain the inflammation process with approaches that protect and reconstitute oligodendrocyte density would be essential to pave the way of myelin repair. A critical signal for oligodendrocytes is insulin-like growth factor-1 (IGF-1), which promotes their development and ultimately myelin formation. PTEN inhibits the phosphoinositide 3-kinase (PI3K)/Akt signaling, a convergence downstream pathway for growth factors such as IGF-1. In this report, we temporarily inhibited PTEN activity by treating rat and human oligodendrocyte progenitors (OLPs) cultured alone or with dorsal root ganglion neurons (DRGNs) with bisperoxovanadium (phen). Our findings show that phen potentiates IGF-1 actions by increasing proliferation of OLPs in a concentration-dependent manner, and caused a sustained and time-dependent activation of the main pathways: PI3K/Akt/mammalian target of rapamycin (mTOR) and MEK/ERK. At low concentrations, IGF-1 and phen stimulated the differentiation of rat and human OLPs. Concordantly, the PTEN inhibitor together with IGF-1 robustly augmented myelin basic protein accumulation in rat newborn and human fetal OLGs co-cultured with DRGNs in a longer timeframe by promoting the elaboration of organized myelinated fibers as evidenced by confocal microscopy. Thus, our results suggest that a transient suppression of a potential barrier for myelination in combination with other therapeutic approaches including growth factors may be promising to improve the functional recovery of CNS injuries.

An estimated quarter of the world's population possesses an infection caused by gastrointestinal nematodes, which induce a Th2 type immune response. Concomitant infection of nematodes with Mycobacterium tuberculosis, which induces a predominantly Th1 type response, is very frequent in tropical and subtropical regions. This study examined immune responses of BALB/c mice infected with Strongyloides venezuelensis and then co-infected with Mycobacterium bovis. The number of worms in the intestine, eggs in feces, cytokine production in lungs and intestine and the expression of CD80, CD86, CTLA-4 and CD28 cell markers on pulmonary cells were analysed. Our results indicate that co-infected mice had an increased parasite burden, which correlates with elevated IFN-gamma and IL-10 cytokine production and decreased IL-4 and IL-13. Moreover, decreased expression of CD80 and increased expression of CTLA-4 were observed in co-infected mice. Our data point out that susceptibility to Strongyloides venezuelensis infection is increased by Mycobacterium bovis co-infection, resulting in higher parasite survival.

The immunological activity of macrophages against pathogens in hosts includes the phagocytosis and the production of nitric oxide. We report herein the investigation of the effect of 6‐carboxymethylthiopurine on nitric oxide production by murine macrophages as well as its effect on the cell viability and proliferation after stimulus with Mycobacterium bovis bacille Calmette–Guérin, interferon‐gamma or a combination of both. J774A.1 macrophages stimulated or not by bacille Calmette–Guérin (20 μg/mL), interferon‐gamma or both, were cultured in the presence of 6‐carboxymethylthiopurine (125, 250 and 500 μm). Nitric oxide production was measured by the Griess method and cell viability/proliferation by the diphenyltetrazolium assay [3‐(4, 5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide]. We observed an increase of J774A.1 cell proliferation after stimulus with bacille Calmette–Guérin at 125, 250 and 500 μm (69.1, 124.0 and 89.7%, respectively) and with interferon‐gamma at 125 and 250 μm (64.8% and 61.7%, respectively) (p < 0.05). In all cultures treated with 6‐carboxymethylthiopurine, interferon‐gamma‐activated nitric oxide production by J774A.1 cells decreased as well as when subjected to interferon‐gamma plus bacille Calmette–Guérin stimuli at 500 μm (p < 0.05). Altogether these data point to an anti‐inflammatory effect of 6‐carboxymethylthiopurine on stimulated macrophages.