Antonio Ciaramella

The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines.

Although poststroke depression is unlikely to represent a single disorder and numerous etiologies for different kinds of poststroke depression will likely emerge as the result of future research, we believe that a number of poststroke depressive disorders are likely to be the result of specific changes in brain pathology and neurophysiology. Nevertheless, there are relatively few hypotheses about the pathophysiology of poststroke depression. This paper, therefore, proposes a new hypothesis for poststroke depression involving increased production of proinflammatory cytokines resulting from brain ischemia in cerebral areas linked to the pathogenesis of mood disorders. This paper reviews the evidence supporting the hypothesis that proinflammatory cytokines are involved in the occurrence of stroke as well as mood disorders linked to the brain damage. The increased production of proinflammatory cytokines such as IL-1β, TNF-α or IL-18 resulting from stroke may lead to an amplification of the inflammatory process, particularly in limbic areas, and widespread activation of indoleamine 2,3-dioxygenase (IDO) and subsequently to depletion of serotonin in paralimbic regions such as the ventral lateral frontal cortex, polar temporal cortex and basal ganglia. The resultant physiological dysfunction may lead to poststroke depression. Future investigations may explore this hypothesis through more extensive studies on the role of proinflammatory cytokines, such as IL-1β, TNF-α or even IL-18, in patients with poststroke depression.

IL-18 cDNA vaccination protects mice from spontaneous lupus-like autoimmune disease

The lupus-like autoimmune syndrome of MRL/Mp-Tnfrsf6lpr (lpr) mice is characterized by progressive lymphadenopathy and autoantibody production, leading to early death from renal failure. Activation of T helper lymphocytes is one of the events in the pathogenesis of the disease in these mice and likely in human systemic lupus erythematosus. Among T helper lymphocytedependent cytokines, IFN-γ plays a pivotal role in the abnormal cell activation and the fatal development of the lpr disease. IL-18, an inducer of IFN-γ in T lymphocytes and natural killer cells, may contribute to the disease because cells from lpr mice are hypersensitive to IL-18 and express high levels of IL-18. To assess the contribution of IL-18 to the pathogenesis in the animal model, in vivo inhibition of IL-18 was attempted. Young lpr mice were vaccinated against autologous IL-18 by repeated administration of a cDNA coding for the murine IL-18 precursor. Vaccinated mice produced autoantibodies to murine IL-18 and exhibited a significant reduction in spontaneous lymphoproliferation and IFN-γ production as well as less glomerulonephritis and renal damage. Moreover, mortality was significantly delayed in anti-IL-18-vaccinated mice. These studies support the concept that IL-18 plays a major role in the pathogenesis of the autoimmune syndrome of lpr mice and that a reduction in IL-18 activity could be a therapeutic strategy in autoimmune diseases.

Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) Patients are Characterized by Increased BDNF Serum Levels

Alzheimers disease (AD) is a neurodegenerative disorder characterized by cognitive decline with loss of memory. In the last years there has been a great interest on the early phases of AD, trying to identify the pathogenic mechanisms of AD and define early treatment modalities. In particular, Mild Cognitive Impairment (MCI) is attractive because it represents a transitional state between normal aging and dementia, although not all MCI patients automatically convert to AD. The neurotrophin brain-derived neurotrophic factor (BDNF) is critical for survival and function of neurons that degenerate in AD and represents a potential neuroprotective agent. However, opposite data on serum levels of BDNF have been reported in AD patients, probably reflecting differences in patient recruitment and stage of the disease. Thus, in this study we measured BDNF serum levels in AD patients (with different degree of severity), MCI patients and healthy subjects. We found that serum BNDF levels were significantly increased in MCI and AD patients when compared to healthy subjects and this increase in AD patients was neither dependent on illness severity, nor on treatment with Acetylcholinesterase inhibitors and/or antidepressant medications. Our findings indicate that BDNF serum levels increase in MCI and AD patients, supporting the hypothesis of an upregulation of BDNF in both preclinical phase of dementia (MCI) and clinical stages of AD. Other studies are necessary to establish a direct link between BDNF peripheral levels and AD longitudinal course, as well as the role of other factors, such as blood cell activation, in determining these events.

Interleukin-18 produced by peripheral blood cells is increased in Alzheimer’s disease and correlates with cognitive impairment

A body of evidence indicates that inflammation plays a pivotal role in AD pathogenesis. IL-18 is a pro-inflammatory cytokine produced in the brain, emerging to be implicated in AD. Although no differences in circulating IL-18 levels were measured between AD patients and controls, a significant increased production of IL-18 was obtained from stimulated blood mononuclear cells of AD patients. This was true particularly in AD subjects carrying the C/C genotype at the -607 position of IL-18 gene promoter. Furthermore, a significant correlation between IL-18 production and cognitive decline was observed in AD patients. Overall, these data indicate that IL-18-related inflammatory pathways, probably also in virtue of polymorphic IL-18 gene influence, are exacerbated in AD patients, and that this cytokine may indeed participate in pathogenic processes leading to dementia.

Interleukin 18 gene polymorphisms predict risk and outcome of Alzheimer’s disease

Background and aim: Inflammation has been extensively implicated in the pathogenesis of Alzheimer’s disease (AD). Although there is evidence of a key role for cytokines in neuroinflammation processes, so far the proinflammatory cytokine interleukin (IL)-18 has not been associated with AD. The aim of this study was to investigate the impact of two polymorphisms of the human IL-18 gene promoter at positions −607 (C/A) and −137 (G/C) on both susceptibility to and progression of AD. Results: The results revealed that the genotype distribution of the −607 (C/A) polymorphism was different between patients with AD and control subjects (χ2 = 7.99, df = 2, p = 0.0184). In particular, carriers of the CC genotype were at increased risk of developing AD (OR 2.33; 95% CI 1.29 to 4.22; p = 0.0052). The observed genotypes were in Hardy–Weinberg equilibrium, as for the −607 polymorphism, whereas the −137 polymorphism appeared in Hardy–Weinberg disequilibrium only in the patient group (p = 0.0061). Finally, in a 2 year follow-up study, the −137 CC genotype was strongly and specifically associated with a faster cognitive decline (F = 4.024; df = 4,192; p = 0.0037 for time by IL-18 −137 G/C group interaction) with no interaction effect with the apolipoprotein E ε4/non-ε4 allele presence. Conclusion: As IL-18 cytokine promoter gene polymorphisms have been previously described to have functional consequences on IL-18 expression, it is possible that individuals with a prevalent IL-18 gene variant have a dysregulated immune response, suggesting that IL-18 mediated immune mechanisms may play a crucial role in AD.

Induction of Apoptosis and Release of Interleukin-1β by Cell Wall-Associated 19-kDa Lipoprotein during the Course of Mycobacterial Infection

Mycobacterium tuberculosis induces apoptosis in human monocyte-derived macrophages (MDMs) during the early stages of infection. We investigated the proapoptotic role of cell wall-associated mycobacterial 19-kDa lipoprotein and the possible association between 19-kDa lipoprotein signaling and production of proinflammatory cytokines. Purified mycobacterial 19-kDa lipoprotein, 19-kDa lipoprotein-expressing M. smegmatis (M. smegmatis 19+), 19-kDa lipoprotein knockout (KO) M. tuberculosis, and 19-kDa lipoprotein KO M. bovis bacille Calmette-Guerin (BCG) strains were analyzed for their ability to induce apoptosis in MDMs. The 19-kDa lipoprotein and infection with M. smegmatis 19+ induced apoptosis in MDMs. M. tuberculosis and BCG KO strains had significantly decreased abilities to induce apoptosis. The 19-kDa lipoprotein proapoptotic signal was mediated by Toll-like receptor 2 but not by tumor necrosis factor-alpha. Only the release of interleukin (IL)-1 beta was decreased after infection with 19-kDa lipoprotein KO strains. These findings indicate that the 19-kDa lipoprotein is the main signal required to trigger both apoptosis and the release of IL-1 beta during the early stages of mycobacterial infection.

Interleukin-18, From Neuroinflammation to Alzheimer's Disease

A large body of evidence on brain development and ageing has revealed that inflammatory processes profoundly affect brain functions during life span of mammalians, including humans. Activation of innate immune mechanisms leading to pro-inflammatory cytokine up-regulation is involved in devastating and disabling human brain illnesses, as Alzheimers disease (AD), a progressive neurodegenerative disease that causes dementia in the elderly. Emerging data indicates that the cytokine Interleukin (IL)-18, one of the key mediator of inflammation and immune response, has relevance in the physiopathological processes of the brain, by ultimately influencing the integrity of neurons and putatively contributing to AD. In this review, the relationship between specific IL-18-mediated processes and AD neurodegeneration is summarized and clinical studies pointing to a role of the cytokine in the pathology are discussed. Altogether, the presented data indicate that a more complete knowledge of the molecular mechanisms underlying IL-18 implication in neuroinflammatory and neurodegenerative pathways could contribute toward the development of new therapeutic strategies for AD.

Dendritic cells derived from BCG-infected precursors induce Th2-like immune response.

Human monocytes can differentiate into dendritic cells (DCs) according to the nature of environmental signals. We tested here whether the infection with the live tuberculosis vaccine bacillus Calmette‐Guerin (BCG), which is known to be limited in preventing pulmonary tuberculosis, modulates monocyte and DC differentiation. We found that monocytes infected with BCG differentiate into CD1a– DCs (BCG‐DCs) in the presence of granulocyte macrophage‐colony stimulating factor and interleukin (IL)‐4 and acquired a mature phenotype in the absence of maturation stimuli. In addition, BCG‐DCs produced proinflammatory cytokines (tumor necrosis factor α, IL‐1β, IL‐6) and IL‐10 but not IL‐12. BCG‐DCs were able to stimulate allogeneic T lymphocytes to a similar degree as DCs generated in the absence of infection. However, BCG‐DCs induced IL‐4 production when cocultured with human cord‐blood mononuclear cells. The induction of IL‐4 production by DCs generated by BCG‐infected monocytes could explain the failure of the BCG vaccine to prevent pulmonary tuberculosis.

Increased Pro-Inflammatory Response by Dendritic Cells from Patients with Alzheimer's Disease

Alzheimers disease (AD) is characterized by abnormal accumulation of amyloid-beta peptide (Abeta) into extracellular fibrillar deposits, paralleled by chronic neuroinflammatory processes. Although Abeta seems to be causative in AD brain damage, the role of the immune system and its mechanisms still remain to be clarified. We have recently shown that normal monocyte-derived dendritic cells (MDDCs), when differentiated in the presence of Abeta1-42, acquire an inflammatory phenotype and a reduced antigen presenting ability. Here we studied MDDCs derived from AD patients in comparison with MDDCs obtained from healthy control subjects (HC). MDDCs from AD patients, at variance with HC-derived cells, were characterized by an augmented cell recovery, a consistent increase in the expression of the pro-inflammatory ICAM-1 molecule, a decrease in the expression of the co-stimulatory CD40 molecule, and an impaired ability to induce T cell proliferation. Furthermore, MDDCs from AD produced higher amounts of IL-6 than HC-derived cells, confirming the more pronounced pro-inflammatory features of these cells in AD patients. Consistent results have been also obtained with monocytes, the MDDC precursors. In fact, while unstimulated monocytes do not appear to be different in AD and HC, after stimulation with lipopolysaccharide, AD monocytes overexpressed ICAM-1 with respect to controls, suggesting that common pathways of monocyte activation and MDDC differentiation are altered in AD. Overall, these findings show that AD-linked dysregulated immune mechanisms exist, which lead to dendritic cell-mediated over-activation of inflammation and impaired antigen presentation, thus supporting the view that immune cell activation could play an important role in AD pathogenesis.

Proinflammatory cytokines in the course of Mycobacterium tuberculosis-induced apoptosis in monocytes/macrophages.

Mycobacterium tuberculosis (MTB) can induce apoptosis in monocytes/macrophages both in vitro and in vivo, and this phenomenon is associated with mycobacterial survival. The present study addresses the possibility that apoptotic and inflammatory pathways could coexist through a caspase-1-mediated mechanism. In this context, a caspase-1 inhibitor (YVAD), but not caspase-3 (DEVD) or caspase-4 (LEVD) inhibitors, was able to strongly inhibit MTB-induced apoptosis. Moreover, caspase-1 activity was confirmed by the increased maturation of interleukin (IL)-1beta. Of interest, IL-1beta and tumor necrosis factor (TNF)-alpha were produced massively in the course of infection, and both were inhibited by YVAD pretreatment. To determine whether TNF-alpha was produced actively by apoptotic cells, the intracytoplasmatic cytokine content and apoptotic phenotype were analyzed at the single-cell level. Results showed a progressive increase of TNF-alpha production in annexin V-positive cells. These results indicate that MTB-induced apoptosis is associated with proinflammatory cytokine production.