Papers by Pranoti Mandrekar
Alcohol consumption inhibits accessory cell function and Ag-specific T cell responses. Myeloid de... more Alcohol consumption inhibits accessory cell function and Ag-specific T cell responses. Myeloid dendritic cells (DCs) coordinate innate immune responses and T cell activation. In this report, we found that in vivo moderate alcohol intake (0.8 g/kg of body weight) in normal volunteers inhibited DC allostimulatory capacity. Furthermore, in vitro alcohol treatment during DC differ- entiation significantly reduced allostimulatory activity in
Alcohol use has been shown to decrease monocyte antigen presentation capacity and inflamma- tory ... more Alcohol use has been shown to decrease monocyte antigen presentation capacity and inflamma- tory cytokine production, thereby increasing susceptibil. ity to infections. Here, we demonstrate that in vitro acute treatment of normal monocytes with pharmacological doses of ethanol can decrease superantigen (Staphylococ- cu.c enterotoxins B (SEB) and A (SEA)).induced T cell proliferation. Furthermore, ethanol treatment (25-100 mM) significantly inhibited SEA-
Alcoholism-clinical and Experimental Research, 2002
BACKGROUND: Acute alcohol treatment blocks inflammatory cytokines via inhibition of NF-kappaB in ... more BACKGROUND: Acute alcohol treatment blocks inflammatory cytokines via inhibition of NF-kappaB in monocytes in the presence of ongoing IkappaBalpha degradation, suggesting regulation of NF-kappaB activation downstream of IkappaBalpha degradation. DNA binding of NF-kappaB has been suggested to be regulated by other nuclear regulatory factors, including the glucocorticoid receptor (GR). Here, we show for the first time that acute alcohol (25
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 2007
Acute alcohol use is associated with impaired immune responses and decreased proinflammatory cyto... more Acute alcohol use is associated with impaired immune responses and decreased proinflammatory cytokine production. Our earlier studies have shown that acute alcohol intake inhibits NF-kappaB DNA binding in an IkappaBalpha-independent manner. We report using human peripheral blood monocytes and Chinese hamster ovary cells transfected with CD14 cells that acute alcohol treatment in vitro exerts NF-kappaB inhibition by disrupting phosphorylation of p65. Immunoprecipitation of p65 and IkappaBalpha revealed that acute alcohol exposure for 1 h decreased NF-kappaB-IkappaBalpha complexes in the cytoplasm. Phosphorylation of p65 at Ser(536) is mediated by IkappaB kinase (IKK)beta and is required for NF-kappaB-dependent cellular responses. We show that acute alcohol treatment decreased LPS-induced IKKalpha and IKKbeta activity resulting in decreased phosphorylation of p65 at Ser(536). Furthermore, nuclear expression of IKKalpha increased after alcohol treatment, which may contribute to inhibit...
Journal of immunology (Baltimore, Md. : 1950), 2004
Alcohol consumption inhibits accessory cell function and Ag-specific T cell responses. Myeloid de... more Alcohol consumption inhibits accessory cell function and Ag-specific T cell responses. Myeloid dendritic cells (DCs) coordinate innate immune responses and T cell activation. In this report, we found that in vivo moderate alcohol intake (0.8 g/kg of body weight) in normal volunteers inhibited DC allostimulatory capacity. Furthermore, in vitro alcohol treatment during DC differentiation significantly reduced allostimulatory activity in a MLR using naive CD4(+) T cells, and inhibited tetanus toxoid Ag presentation by DCs. Alcohol-treated DCs showed reduced IL-12, increased IL-10 production, and a decrease in expression of the costimulatory molecules CD80 and CD86. Addition of exogenous IL-12 and IL-2, but not neutralization of IL-10, during MLR ameliorated the reduced allostimulatory capacity of alcohol-treated DCs. Naive CD4(+) T cells primed with alcohol-treated DCs showed decreased IFN-gamma production that was restored by exogenous IL-12, indicating inhibition of Th1 responses. Fu...
Journal of clinical immunology, 1999
Chronic alcohol use is associated with impaired immunity and host defense. Even acute ethanol tre... more Chronic alcohol use is associated with impaired immunity and host defense. Even acute ethanol treatment both in vitro and in vivo has been shown to result in decreased inflammatory cytokine production. However, the potential immunoregulatory effects of acute, moderate alcohol use are yet to be fully explored. Here we show that in vitro acute alcohol treatment of normal blood monocytes resulted in a significant, dose-dependent (25-100 mM) attenuation of staphylococcus enterotoxin B (SEB), phytohemagglutinin (PHA), or IFNG-induced monocyte IL-8 and MCP-1 production (P < 0.01). Likewise, ethanol (100 mM) in vitro reduced MCP-1 levels in response to SEB, PHA, or IFNG stimulation in mononuclear cells (31-62% reduction). Furthermore, acute alcohol consumption (0.85 g/kg body weight) significantly attenuated SEB-or LPS-induced IL-8 and MCP-1 levels in whole-blood samples obtained 4 hr after alcohol consumption from normal nonalcoholic individuals (P < 0.01). RANTES and MIP-1B were only minimally inhibited (16-25% inhibition) by in vitro ethanol (100 mM) in mononuclear cells, suggesting that ethanol may have a selective effect on the regulation of various chemokines. These results demonstrate that acute alcohol, in vivo as well as in vitro, attenuates monocyte-derived chemokine production in response to a subsequent immune challenge. Our data show for the first time that activation of nuclear regulatory factor kB (NF-kB), a common regulator binding in the promoter region of IL-8 and MCP-1 genes, is inhibited by acute ethanol (25 mM) treatment in SEB-stimulated human monocytes. These results imply that inhibition of NF-kB activation may be one of the intracellular mechanisms for the ethanol-induced inhibition of IL-8 and MCP-1 production in monocytes. Thus, impaired chemokine (particularly MCP-1 and IL-8) induction upon an immune challenge is likely to contribute to compromised host defense after acute alcohol consumption and may also affect progression of diseases such as atherosclerosis or HIV infection where chemokines contribute to progression of the disease.
International journal of immunopharmacology, 1998
IL-12, a monocyte-derived cytokine, is pivotal in activation of cellular immune response and infl... more IL-12, a monocyte-derived cytokine, is pivotal in activation of cellular immune response and inflammation. Both inflammatory response and cellular immunity are impaired by acute ethanol consumption. Here, we found that in vitro acute ethanol treatment (25-100 mM) results in a dose-dependent and significant increase of IL-12 in IFN-gamma (100 U/ml) plus Staphylococcal enterotoxin B (SEB; 1 microg/ml) stimulated monocytes and mononuclear cells but not in unstimulated cells from non-alcoholic blood donors. There was significantly greater IL-12 production in the MNC population compared to isolated Mphi (P < 0.001). Prevention of monocyte surface contact with either purified T lymphocytes or monocyte-depleted MNC resulted in a significant, 65+/-20%, decrease in IL-12 production regardless of IFN-gamma, SEB or ethanol stimulation suggesting that Mphi T-cell surface contact provides an additional signal for IL-12 production. In addition to cell surface contact, soluble mediators, partic...
Most pathogens express ligands for multiple TLRs that share common downstream signaling. In this ... more Most pathogens express ligands for multiple TLRs that share common downstream signaling. In this study, we investigated the effects of acute alcohol on inflammatory pathways induced by TLR2 or TLR4 ligands and their combination. In human monocytes, alcohol attenuated TLR4- but not TLR2-induced TNF-alpha protein and mRNA levels and NF-kappaB activation. In contrast, acute alcohol augmented TNF-alpha production when both
Stimulation of monocytes (MO) through receptors for the Fc region of immunoglobulin G (FcgammaR) ... more Stimulation of monocytes (MO) through receptors for the Fc region of immunoglobulin G (FcgammaR) activates a variety of responses, including phagocytosis, antibody (Ab)-dependent cellular cytotoxicity, and production of cytokines. We previously reported that the MO subpopulation that expresses FcgammaR in high density produces high levels of tumor necrosis factor alpha (TNF-alpha) compared with FcgammaR-negative MO. Here, we show that cross-linking
BACKGROUND: Immunosuppression associated with chronic alcohol use is characterized by reduced ant... more BACKGROUND: Immunosuppression associated with chronic alcohol use is characterized by reduced antigen-specific T-cell response and impaired delayed type hypersensitivity. Increasing evidence suggests in chronic alcohol consumption models that reduced antigen-specific T-cell proliferation is due to insufficient accessory cell function. Accessory cell function, a critical step in recognition of viral antigens, is reduced in chronic hepatitis C. The severity of hepatitis
Seminars in Liver Disease, 2007
Inflammation is a pathogenic component of various types of acute and chronic liver diseases, and ... more Inflammation is a pathogenic component of various types of acute and chronic liver diseases, and it contributes to progressive liver damage and fibrosis. Cells of the innate immune system initiate and maintain hepatic inflammation though mediator production as a result of their activation by pathogen-derived products recognized by pattern recognition receptors. Innate immune cells, particularly dendritic cells, have a pivotal role in sensing pathogens and initiating adaptive immune responses by activation and regulation of T-lymphocyte responses. Although the liver provides a &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;tolerogenic&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; immune environment for antigen-specific T-cells, activation of Kupffer cells, recruited macrophages, and inflammatory cells results in production of cytokines and chemokines that can lead to prolonged inflammation, hepatocyte damage, and/or cholestasis. The specificity of Toll-like receptors and the mechanisms of innate immune cell activation are discussed in relation to acute and chronic liver injury including viral, alcoholic, nonalcoholic, and drug-induced hepatitis.
BACKGROUND/AIMS: Alcohol use alters inflammatory cell responses. While alcohol has direct effects... more BACKGROUND/AIMS: Alcohol use alters inflammatory cell responses. While alcohol has direct effects on pancreatic acinar cells, activation of inflammatory cells is a major component of the pathology of alcoholic pancreatitis. METHODS: The effects of acute or chronic alcohol exposure were evaluated in human monocytes on the production of TNFalpha or IL-10 production, pro-inflammatory gene and nuclear factor-kappaB (NF-kappaB) activation. RESULTS: Moderate, acute alcohol consumption or equivalent doses of alcohol in vitro had anti-inflammatory effects on monocyte activation via inhibition of pro-inflammatory genes and NF-kappaB activation, inhibition of TNFalpha production and augmentation of the anti-inflammatory cytokine, IL-10. In contrast, acute alcohol treatment augmented NF-kappaB activation and TNFalpha production and inhibited IL-10 levels in the presence of complex stimulation with combined TLR2 and TLR4 ligands. Prolonged alcohol exposure also resulted in an increase in NF-kap...
Journal Of Investigative Medicine, 2001
Myeloid dendritic cells (DCs) are pivotal in the recognition of alloantigens and, therefore, in t... more Myeloid dendritic cells (DCs) are pivotal in the recognition of alloantigens and, therefore, in the induction of allograft rejection. Induction of alloreactive T cell proliferation by myeloid DCs depends on the maturation of DCs, the expression of costimulatory molecules, and the cytokine environment. This study investigated the effects of tacrolimus and cyclosporine A (CsA) on DC maturation and allostimulatory capacity. Myeloid DCs were propagated from normal blood monocytes with interleukin (IL) 4 and GM-CSF for 7 days in the presence or absence of tacrolimus (FK506; 10 nM) or CsA (1 microg/mL). Exposure of DCs during maturation to tacrolimus or CsA resulted in no significant change in the expression of DC phenotypic markers, including CD80, CD86, and HLA Class I and II antigens determined by flow cytometry. T cell proliferation in one-way, mixed-leukocyte reaction experiments revealed a decreased allostimulatory capacity of DCs that matured in the presence of tacrolimus or CsA compared with untreated controls (P&lt;0.02). Production of inflammatory cytokines, tumor necrosis factor alpha (P&lt;0.04) and IL-12 (P&lt;0.04) in response to lipopolysaccharide (1 microg/mL) or staphylococcal enterotoxin B (1 microg/mL) induction was significantly reduced in DCs exposed to tacrolimus or CsA during maturation. In contrast, production of the immuninhibitory cytokine IL-10 was not decreased in tacrolimus- or CsA-treated DCs. These results suggest that tacrolimus and CsA inhibit the allostimulatory capacity of in vitro-generated myeloid DCs without significant effects on DC phenotypic maturation. Decreased production of IL-12 and tumor necrosis factor alpha, but not of IL-10, is likely to contribute to the impaired accessory-cell function of tacrolimus- and CsA-treated DCs. Thus, tacrolimus and CsA can inhibit recognition of alloantigens by decreasing the accessory-cell capacity of monocyte-derived myeloid DCs.
Journal of Hepatology, 2006
Background/Aims: Toll-like receptors (TLR) recognize pathogens and regulate innate immune activat... more Background/Aims: Toll-like receptors (TLR) recognize pathogens and regulate innate immune activation. Here, we investigated the roles of TLR9 and the common TLR adaptor, MyD88, in liver injury.
Journal of Hepatology, 2009
The pathogenesis of alcoholic liver injury involves interactions of several intracellular signall... more The pathogenesis of alcoholic liver injury involves interactions of several intracellular signalling pathways in different cell types of the liver. Alcohol-induced sensitization of liver macrophages to portal endotoxin / lipopolysaccharide (LPS) is considered a hallmark of alcoholic liver disease (ALD). Intracellular mechanisms associated with LPS-induced signalling play a crucial role in the initiation and progression of alcoholic liver injury, and are being extensively explored. LPS recognition by Toll-like receptor 4 (TLR4) on macrophages and other cell types in the liver, activation of downstream signalling pathways culminating in activation of transcription factors such as NFjB, AP-1 leads to increased inflammatory cytokine production in ALD. In addition, LPS-induced MAPK such as ERK and p38 also contribute to liver injury. The importance of alcohol-induced reactive oxygen species and interactions with TLR pathways in macrophages leading to inflammation is becoming increasingly evident. Collectively, these signalling pathways induce pro-and anti-inflammatory cytokines that play an important role in ALD. In this review we describe the key signalling intermediates leading to alcohol-induced inflammation in alcoholic liver disease. Ó
Journal of Clinical Immunology, 1994
The hypothesis that acute ethanol uptake plus trauma can synergize to increase immunosuppression ... more The hypothesis that acute ethanol uptake plus trauma can synergize to increase immunosuppression was tested. We found that, unlike non-alcohol-exposed patients, patients with acute alcohol use prior to trauma have a transient decrease in monocyte tumor necrosis factor alpha (TNF alpha) production during the very early postinjury (0-3 days) period. However, TNF alpha production by these alcohol-exposed patients&#39; monocytes (M0) became hyperelevated late postinjury (&gt; 9 days). Consequently, these massively elevated M0 TNF alpha levels can contribute to posttrauma immunosuppression after acute alcohol use. We also demonstrate that normal monocyte activation with the superantigen, Staphylococcus enterotoxin B (SEB), results in a preferential induction of cell-associated M0 TNF alpha production, described as characteristic of immunosuppressed trauma patients. Acute in vitro ethanol treatment down-regulated the elevated TNF alpha production by trauma patients&#39; M0 after either SEB, muramyl-dipeptide (MDP), interferon-gamma plus MDP, or lipopolysaccharide (LPS) stimulation. Both SEB- and LPS-induced TNF alpha mRNA induction was inhibited by acute alcohol treatment in normal M0, indicating that ethanol can regulate cytokine gene expression. An additional immunosuppressive effect of acute ethanol&#39;s stimulation was suggested by its induction of elevated transforming growth factor beta production in trauma patients&#39; activated M0.
International Immunology, 1999
Alcohol use is typically associated with impaired immunity and increased host susceptibility to i... more Alcohol use is typically associated with impaired immunity and increased host susceptibility to infection, partially due to decreased inflammatory response. Acute ethanol exposure has been shown to down-regulate monocyte production of inflammatory cytokines. Activation of the pluripotent transcription factor NFκB is a pivotal step in the induction of inflammatory cytokines, chemokines and growth factors. Therefore, we hypothesized that alcohol may alter NFκB activation, thus providing a mechanism for the decreased inflammatory cytokine production by monocytes after acute alcohol treatment. We show here for the first time that alcohol inhibits lipopolysaccharide (LPS)-induced NFκB activation in human monocytes by decreasing DNA binding of the p65/p50 heterodimer as seen in electrophoretic mobility shift and supershift assays. We also demonstrate that alcohol prevents LPS-induced nuclear translocation of p65 and to a lesser extent that of the p50 subunits. NFκB activation is regulated via phosphorylation and proteolytic degradation of IκB. Thus, we investigated the effect of acute ethanol treatment on IκB in human monocytes. Alcohol did not prevent LPS-induced IκBα degradation but decreased the levels of phospho-specific IκBα (Ser32). Finally, for the first time we show that de novo protein synthesis is necessary to bring about the ethanol-mediated inhibition of LPS-induced NFκB activation. Consequently, these results suggest that physiologically relevant concentrations of alcohol interfere with NFκB activation and thereby may affect the regulation of NFκB-controlled gene activation.
Hepatology, 2004
Lipopolysaccharide (LPS) triggers cytokine production through Toll-like receptor 4 (TLR4), which ... more Lipopolysaccharide (LPS) triggers cytokine production through Toll-like receptor 4 (TLR4), which shares downstream signaling pathways with TLR2. We investigated the roles of TLR2 and TLR4 in Propionibacterium acnes (P. acnes)-primed, LPS-induced liver damage using selective TLR ligands. Stock LPS induced interleukin 8 in both TLR4-and TLR2-expressing human embryonic kidney (HEK) 293 cells. Purified LPS (TLR4 ligand) activated HEK/TLR4 cells, while peptidoglycan and lipoteichoic acid (TLR2 ligands) activated HEK/TLR2 cells, respectively. In mice, P. acnes priming resulted in increased liver messenger RNA (mRNA) and serum levels of tumor necrosis factor ␣, interleukin 12, and interferon ␥ (IFN-␥) by both stock LPS and purified LPS challenges compared with nonprimed controls. In contrast, P. acnes failed to sensitize to TLR2 ligands (peptidoglycan ؉ lipoteichoic acid). In the liver, P. acnes-priming was associated with up-regulation of TLR4 and MD-2 proteins, and subsequent LPS challenge further increased MD-2 and CD14 mRNA levels. The lack of sensitization to TLR2 ligands by P. acnes correlated with no increase in hepatic TLR1 or TLR6 mRNA. In vitro, P. acnes pretreatment desensitized RAW macrophages to a secondary stimulation via both TLR2 and TLR4. However, IFN-␥ could selectively prevent desensitization to TLR4 but not to TLR2 ligands. Furthermore, P. acnes induced production of IFN-␥ in vivo as well as in isolated splenocytes. In vitro, P. acnes-primed Hepa 1-6 hepatocytes but not RAW macrophages produced increased MD-2 and CD14 mRNA levels after an LPS challenge. In conclusion, P. acnes priming to selective TLR4-mediated liver injury is associated with up-regulation of TLR4 and MD-2 and is likely to involve IFN-␥ and prevent TLR4 desensitization by P. acnes. (HEPATOLOGY 2004;40:555-564.)
Hepatology, 2006
Pattern recognition receptors (PRRs) function as sensors of microbial danger signals enabling the... more Pattern recognition receptors (PRRs) function as sensors of microbial danger signals enabling the vertebrate host to initiate an immune response. PRRs are present not only in immune cells but also in liver parenchymal cells and the complexity of the cell populations provide unique aspects to pathogen recognition and tissue damage in the liver. This review discusses the role of different PRRs in pathogen recognition in the liver, and focuses on the role of PRRs in hepatic inflammation, cholestasis, ischemia, repair and fibrosis. PRRs as novel therapeutic targets are evaluated. (HEPATOLOGY 2006;44:287-298.)
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Papers by Pranoti Mandrekar