Production of nerve growth factor (NGF) was assessed in cultures of human T and B lymphocytes and macrophages. NGF was constitutively produced by B cells only, which also expressed surface p140trk-A and p75NGFR molecules and hence efficiently bound and internalized the cytokine. Neutralization of endogenous NGF caused disappearance of Bcl-2 protein and apoptotic death of resting lymphocytes bearing surface IgG or IgA, a population comprising memory cells, while surface IgM/IgD "virgin" B lymphocytes were not affected. In vivo administration of neutralizing anti-NGF antibodies caused strong reduction in the titer of specific IgG in mice immunized with tetanus toxoid, nitrophenol, or arsonate and reduced numbers of surface IgG or IgA B lymphocytes. Thus, NGF is an autocrine survival factor for memory B lymphocytes.

Undifferentiated cells and embryos express high levels of endogenous non-telomerase reverse transcriptase (RT) of retroposon/retroviral origin. We previously found that RT inhibitors modulate cell growth and differentiation in several cell lines. We have now sought to establish whether high levels of RT activity are directly linked to cell transformation. To address this possibility, we have employed two different approaches to inhibit RT activity in melanoma and prostate carcinoma cell lines: pharmacological inhibition by two characterized RT inhibitors, nevirapine and efavirenz, and downregulation of expression of RT-encoding LINE-1 elements by RNA interference (RNAi). Both treatments reduced proliferation, induced morphological differentiation and reprogrammed gene expression. These features are reversible upon discontinuation of the anti-RT treatment, suggesting that RT contributes to an epigenetic level of control. Most importantly, inhibition of RT activity in vivo antagonized tumor growth in animal experiments. Moreover, pretreatment with RT inhibitors attenuated the tumorigenic phenotype of prostate carcinoma cells inoculated in nude mice. Based on these data, the endogenous RT can be regarded as an epigenetic regulator of cell differentiation and proliferation and may represent a novel target in cancer therapy.

Dendritic cells (DCs) show a remarkable functional plasticity in the recognition of Aspergillus fumigatus and orchestrate the antifungal immune resistance in the lungs. Here, we show that thymosin alpha 1, a naturally occurring thymic peptide, induces functional maturation and interleukin-12 production by fungus-pulsed DCs through the p38 mitogen-activated protein kinase/nuclear factor (NF)-kappaB-dependent pathway. This occurs by signaling through the myeloid differentiation factor 88-dependent pathway, involving distinct Toll-like receptors. In vivo, the synthetic peptide activates T-helper (Th) cell 1-dependent antifungal immunity, accelerates myeloid cell recovery, and protects highly susceptible mice that received hematopoietic transplants from aspergillosis. By revealing the unexpected activity of an old molecule, our finding provides the rationale for its therapeutic utility and qualify the synthetic peptide as a candidate adjuvant promoting the coordinated activation of the innate and adaptive Th immunity to the fungus.

A growing body of epidemiologic and experimental data point to chronic bacterial and viral infections as possible risk factors for neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Infections of the central nervous system, especially those characterized by a chronic progressive course, may produce multiple damage in infected and neighbouring cells. The activation of inflammatory processes and host immune responses cause chronic damage resulting in alterations of neuronal function and viability, but different pathogens can also directly trigger neurotoxic pathways. Indeed, viral and microbial agents have been reported to produce molecular hallmarks of neurodegeneration, such as the production and deposit of misfolded protein aggregates, oxidative stress, deficient autophagic processes, synaptopathies and neuronal death. These effects may act in synergy with other recognized risk factors, such as aging, concomitant metabolic diseases and the host’s specific genetic signature. This review will focus on the contribution given to neurodegeneration by herpes simplex type-1, human immunodeficiency and influenza viruses, and by Chlamydia pneumoniae.

We have previously shown that the life cycles of several viruses are influenced by host-cell redox states. Reports of the antioxidant activities of the plant polyphenol resveratrol (RV) prompted us to investigate its effects on influenza virus replication in vitro and in vivo. We found that RV strongly inhibited the replication of influenza virus in MDCK cells but that this activity was not directly related to glutathione-mediated antioxidant activity. Rather, it involved the blockade of the nuclear-cytoplasmic translocation of viral ribonucleoproteins and reduced expression of late viral proteins seemingly related to the inhibition of protein kinase C activity and its dependent pathways. RV also significantly improved survival and decreased pulmonary viral titers in influenza virus-infected mice. No toxic effects were observed in vitro or in vivo. That RV acts by inhibiting a cellular, rather than a viral, function suggests that it could be a particularly valuable anti-influenza drug.

IntroductionThe induction of tolerance is central to the maintenance of immune homeostasis. Not only are dendritic cells (DCs) key elements in the development of immunity, but they also participate in the generation and maintenance of immune tolerance. Many studies have demonstrated a pivotal role for the enzyme indoleamine 2,3-dioxygenase (IDO) in immune regulation during infection, pregnancy, autoimmunity, transplantation, and neoplasia. 1,2 IDO is widely expressed in a variety of human tissues as well as in macrophages and DCs and is induced in inflammatory states via type I or type II IFN signaling. Through localized tryptophan deficiency combined with the release of proapoptotic kynurenines, DCs exert an IDO-dependent homeostatic control over the proliferation and survival of peripheral T cells and promote antigen-specific tolerance. 3,4 Murine plasmacytoid DCs (pDCs), which produce and respond to type I IFNs, have been credited with a unique ability to express functional IDO, implying an important role for these cells in the maintenance of peripheral tolerance. 5 DCs are now being exploited to improve vaccine efficacy. 6 Pathogen-pulsed DCs act, indeed, as a potent fungal vaccine in experimental hematopoietic stem cell transplantation (HSCT). 7 Protection is associated with myeloid and T-cell recovery, the activation of CD4 ϩ T-helper type 1 (Th1) lymphocytes, and the concomitant production of IL-10. This cytokine is required for the induction of regulatory T (Treg) cells, which have important functions in immune homeostasis including the onset of transplantation tolerance, inhibition of inflammation, and prevention of graft-versus-host disease (GVHD) lethality and leukemia relapse. [8][9][10] As tolerance is also one major requirement of a successful immune response to fungi, 11-13 tolerogenic DCs, including pDCs, may be pivotal in the generation of some form of dominant regulation that ultimately controls inflammation, pathogen immunity, and tolerance in transplant recipients. 14 Thymosin ␣1 (T␣1) is a naturally occurring thymic peptide 15 that promotes activation and cytokine production in human and murine mature DCs by signaling through Toll-like receptors (TLRs), including TLR9. 16 By influencing the balance of IL-12-and IL-10-producing DCs, T␣1 acts as an immune regulator capable of inducing protective immunity to Aspergillus fumigatus. 16 TLR9 stimulation can also lead to IDO activation via mechanisms including autocrine type I IFN signaling 17,18 and can promote pDC-mediated generation of CD4 ϩ CD25 ϩ cells, 19 which are an essential component of the IDO-dependent protective immunity to fungi. [11][12][13] We hypothesized that T␣1 could affect the balance of immunity and tolerance by DCs and the generation of Treg cells. We assessed here the effects of T␣1 on deriving DCs from bone marrow (murine) or peripheral blood (human) L.R. and P.P. devised the study, critically evaluated the data at regular intervals, and drafted the paper. L.R. takes responsibility for integrity of the work as a whole. K.P....

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An overproduction of reactive oxygen species (ROS) mediated by NADPH oxidase 2 (NOX2) has been related to airway inflammation typical of influenza infection. Virus-induced oxidative stress may also control viral replication, but the mechanisms underlying ROS production, as well as their role in activating intracellular pathways and specific steps of viral life cycle under redox control have to be fully elucidated. In this study, we demonstrate that influenza A virus infection of lung epithelial cells causes a significant ROS increase that depends mainly on NOX4, which is upregulated at both mRNA and protein levels, while the expression of NOX2, the primary source of ROS in inflammatory cells, is downregulated. Inhibition of NOX4 activity through chemical inhibitors or RNA silencing blocks the ROS increase, prevents MAPK phosphorylation, and inhibits viral ribonucleoprotein (vRNP) nuclear export and viral release. Overall these data, obtained in cell lines and primary culture, describe a so far unrecognized role for NOX4-derived ROS in activating redox-regulated intracellular pathways during influenza virus infection and highlight their relevance in controlling specific steps of viral replication in epithelial cells. Pharmacological modulation of NOX4-mediated ROS production may open the way for new therapeutic approaches to fighting influenza by targeting cell and not the virus.