Proinflammatory Modulation of the Surface and Cytokine Phenotype of Monocytes in Patients With Acute Charcot Foot

Despite increased information on the importance of an inappropriate inflammatory response in the acute Charcot process, there has been no previous attempt to define the specific pathways that mediate its pathogenesis. Here, the role played by monocytes was analyzed

Climate change effects on phytoplankton depend on cell size and food web structure

We investigated the effects of warming on a natural phytoplankton community from the Baltic Sea, based on six mesocosm experiments conducted 2005–2009. We focused on differences in the dynamics of three phytoplankton size groups which are grazed to a variable extent by different zooplankton groups. While small-sized algae were mostly grazer-controlled, light and nutrient availability largely determined the growth of medium- and large-sized algae. Thus, the latter groups dominated at increased light levels. Warming increased mesozooplankton grazing on medium-sized algae, reducing their biomass. The biomass of small-sized algae was not affected by temperature, probably due to an interplay between indirect effects spreading through the food web. Thus, under the higher temperature and lower light levels anticipated for the next decades in the southern Baltic Sea, a higher share of smaller phytoplankton is expected. We conclude that considering the size structure of the phytoplankton community strongly improves the reliability of projections of climate change effects

1alpha,25-dihydroxyvitamin D3 inhibits CD40L-induced proinflammatoryand immunomodulatory activity in Human Monocytes

CD40 ligand (CD40L) stimulation induces proinflammatory and immunomodulatory activity in monocytes. Here, we report on the effects of the steroid hormone 1a,25-dihydroxyvitamin D3 (1,25D3) on human blood monocytes that have been stimulated with the CD40L ligand. Co-treatment of CD40L-stimulated monocytes with 1,25D3 resulted in reduced production and secretion of tumor necrosis factor (TNF)-a and interleukin (IL)-1b, as well as in reduced expression of the surface co-stimulatory molecules CD80 and CD86. In addition, costimulation of CD4+ T lymphocytes by monocytes co-treated with CD40L and 1,25D3 resulted in reduced cell proliferation and diminished interferon (IFN)-c but enhanced IL-10 production by CD4+ T cells. Finally, 1,25D3 interfered with the ability of CD40L to rescue monocytes from apoptosis induced by serum withdrawal. These findings suggest that 1,25D3 may regulate the interaction of monocytes with T cells or other cell types that express CD40L, thus influencing the outcome of the immune or inflammatory response

Vitamin D3 modulates T lymphocyte responses in hepatitis C virus-infected liver transplant recipients.

BACKGROUND: Aim of the present study was to investigate whether 1,25(OH)(2)D(3) (Vitamin D3) modulates T lymphocyte functions in patients transplanted for hepatitis C virus-related cirrhosis. METHODS: Sixteen patients and ten healthy subjects were investigated. T lymphocytes were activated in vitro in the presence or absence of Vitamin D3 and then the proliferative response and IFN-γ and TNF-α production were assessed. RESULTS: Vitamin D3 potently reduced T-lymphocyte proliferation in a dose-related fashion. Similarly, FACS analysis and ELISA testing demonstrated that Vitamin D3 significantly decreased the response frequency and the response intensity of IFN-γ and TNF-α production in the whole CD3-positive T lymphocyte population as well as in "naive" CD4+ CD45RA+ and "memory" CD4+ CD45RO+ T lymphocyte subsets. The inhibitory effect of Vitamin D3 on T-cell proliferation and cytokine production was not different between patients and controls. No toxic effects were exerted by Vitamin D3 even at the higher concentration used (10nM). Finally, no statistically significant correlation was found between 25(OH)D serum levels and the proliferative response or cytokine production of T lymphocytes from transplanted patients. CONCLUSIONS: This study demonstrates that in patients transplanted for hepatitis C virus-related cirrhosis Vitamin D3 modulates T lymphocyte activation, and provides a rationale for the evaluation of this compound as an immunosuppressive agent in liver-transplanted patients

Upregulation of the inhibitory receptor ILT4 in monocytes from septic patients

Sepsis-induced immune dysfunction is a complex phenomenon that involves both innate and adaptive responses. Upregulation of the inhibitor receptor named immunoglobulin like transcript 4 (ILT4) is crucial to the tolerogenic function of monocytes. Here, ILT4 expression, endotoxin-induced IL-12 and IL-10 production and CD86 expression were investigated in circulating monocytes from 16 patients with severe sepsis and 16 age and sex matched controls. We found that monocytes from patients with severe sepsis express significantly higher levels of ILT4 than monocytes from controls. Upregulation of ILT4 expression appeared to be induced by soluble factors present in the serum of septic patients and directly correlated with the degree of organ dysfunction. ILT4(+) monocytes from septic patients also displayed an alteration in the cytokine response to endotoxin stimulation characterized by reduced IL-12 production and increased IL-10 production, and a reduced expression of the costimulatory molecule CD86. In conclusion, the increased ILT4 expression and IL-10 production and the decreased CD86 expression and IL-12 production indicate that during sepsis monocytes undergo substantial modulation of the surface and cytokine phenotype. These phenotypic changes may interfere with the antigen presenting cell activity of monocytes, which may contribute to the impairment of adaptive immune responses that takes place during sepsi

Dysregulation of immune monocyte responses during sepsis

Introduction: Despite intense efforts, sepsis remains a serious clinical problem, accounting for thousands of deaths every year. Many findings have shown that immune dysfunction in septic patients plays a very important role. Thus, a better understanding of the basic immune alterations in sepsis is needed to appropriately direct therapy. Here we sequentially measured TNFα, IL-1B, IL-6 and IL-10 de novo synthesis by monocytes via multiparametric flow cytometry and monocyte expression of surface molecules that allow effective antigen presentation, in patients with severe sepsis and septic shock up to 12 days after admission. Methods:Twenty-five patients and 15 healthy, age and sex matched control subjects were enrolled. Each patient met the following criteria: an identifiable site of infection; two or more systemic inflammatory response syndrome criteria. Septic shock was defined as severe hypotension that lasts 1 hour, despite adequate fluid resuscitation and pharmacologic intervention with vasopressor agents. Cell stimulation PBMC from patients and controls were cultured for 18 hours in the presence of 100 ng/ml LPS and analysed by FACS to determine cell surface antigen expression and intracellular cytokine production. Results: Cytokine production by monocytes during sepsis Monocytes from septic patients produced significantly higher amounts of IL-1B, TNFα and IL-6, but not IL-10 as compared with controls. In addition, monocytes from patients with septic shock responded to LPS stimulation with increased IL-1B, TNFα and IL-6 production with respect to cells from patients without septic shock. Serum cytokine levels All cytokines were readily detectable in septic patients. Effect of sepsis on surface molecule expression Monocyte CD80, CD86 and HLA-DR expression was significantly decreased in patients with sepsis as compared with healthy subjects. As opposed, the expression of ILT4 was significantly increased in septic patients as compared with healthy controls. Conclusions:It has been postulated that the immune response in sepsis represents the interplay of two contrasting phenomena: the early systemic inflammatory response syndrome followed by the late appearance of a compensatory anti-inflammatory response syndrome. The findings reported here suggest a scenario, characterized by the contemporary development of an intense proinflammatory reaction and a marked alteration of the phenotype of antigen-presenting cells

Indolyl aryl sulphones as HIV-1 non-nucleoside reverse transcriptase inhibitors: synthesis, biological evaluation and binding mode studies of new derivatives at indole-2-carbxamide.

New non-nucleoside reverse transcriptase inhibitors (NNRTIs) that are active against the commonly occurring mutations of HIV are urgently needed for the treatment of AIDS. We synthesized new NNRTIs of the indolyl aryl sulphone (IAS) family, which are endowed with high antiviral potency against HIV-1 wt (wild-type), and the Y181C and K103N-Y181C drug resistant mutant strains. Several new compounds were highly active in lymphocytes infected with primary isolates carrying the K103N-V1081-M184V and L1001-V1081 mutations. The design of new IASs was based on three-dimensional quantitative structure-activity relationship (3D QSAR) studies and docking simulations. A cross-docking study was also undertaken to gain some insights in to the binding mode of the newly synthesized IASs in the wt and mutated isoforms of reverse transcriptase

Sensitivity of different assays for the serological diagnosis of epidermolysis bullosa acquisita: analysis of a cohort of 24 Italian patients.

none10Calabresi V; Sinistro A; Cozzani E; Cerasaro C; Lolicato F; Muscianese M; Parodi A; Didona B; Zambruno G; Di Zenzo G.Calabresi, V; Sinistro, A; Cozzani, EMANUELE CLAUDIO; Cerasaro, C; Lolicato, F; Muscianese, M; Parodi, Aurora; Didona, B; Zambruno, G; Di Zenzo, G

Dysregulation of immune monocyte responses during sepsis

Introduction Despite intense efforts, sepsis remains a serious clinical problem,accounting for thousands of deaths every year. Many findings have shown that immune dysfunction in septic patients plays a very important role. Thus, a better understanding of the basic immune alterations in sepsis is needed to appropriately direct therapy. Here we sequentially measured TNFα, IL-1B, IL-6 and IL-10 de novo synthesis by monocytes via multiparametric flow cytometry and monocyte expression of surface molecules that allow eff ective antigen presentation, in patients with severe sepsis and septic shock up to 12 days after admission. Methods Twenty-fi ve patients and 15 healthy, age and sex matched control subjects were enrolled. Each patient met the following criteria: an identifi able site of infection; two or more systemic inflammatory response syndrome criteria. Septic shock was defined as severe hypotension that lasts 1 hour, despite adequate fluid resuscitation and pharmacologic intervention with vasopressor agents. Cell stimulation PBMC from patients and controls were cultured for 18  hours in the presence of 100 ng/ml LPS and analysed by FACS to determine cell surface antigen expression and intracellular cytokine production. Results Cytokine production by monocytes during sepsis Monocytes from septic patients produced signifi cantly higher amounts of IL-1B, TNFα and IL-6, but not IL-10 as compared with controls. In addition, monocytes from patients with septic shock responded to LPS stimulation with increased IL-1B, TNFα and IL-6 production with respect to cells from patients without septic shock. Serum cytokine levels All cytokines were readily detectable in septic patients. Eff ect of sepsis on surface molecule expression Monocyte CD80, CD86 and HLA- DR expression was signifi cantly decreased in patients with sepsis as compared with healthy subjects. As opposed, the expression of ILT4 was signifi cantly increased in septic patients as compared with healthy controls. Conclusions It has been postulated that the immune response in sepsis represents the interplay of two contrasting phenomena: the early systemic infl ammatory response syndrome followed by the late appearance of a compensatory anti-infl ammatory response syndrome. The fi ndings reported here suggest a scenario, characterized by the contemporary development of an intense proinfl ammatory reaction and a marked alteration of the phenotype of antigen-presenting cells