Biomedical subjects

Swati Joshi-Barve

Publications and source records attributed to Swati Joshi-Barve.

9 recordsLinked to original sources

PubMed2006

Chronic ethanol-mediated decrease in cAMP primes macrophages to enhanced LPS-inducible NF-kappaB activity and TNF expression: relevance to alcoholic liver disease.

Increased plasma and hepatic TNF-alpha activity has been implicated in the pathogenesis of alcoholic liver disease (ALD). We previously reported that monocytes from alcoholic patients show enhanced constitutive as well as LPS-inducible NF-kappaB activation and TNF-alpha production. Studies in monocytes have shown that cAMP plays an important role in regulating TNF-alpha expression, and elevation of cellular cAMP suppresses TNF-alpha production. The effects of chronic ethanol exposure on the cellular levels of cAMP as well as TNF expression in monocytes were examined in vitro and in rat primary hepatic Kupffer cells obtained from a clinically relevant enteral alcohol feeding model of ALD. Chronic ethanol exposure significantly decreased cellular cAMP levels in both LPS-stimulated and unstimulated monocytes. Consistent with the decrease in cAMP levels, ethanol led to an increase in LPS-inducible TNF-alpha production by affecting NF-kappaB activation and induction of TNF mRNA expression, without any change in TNF mRNA stability. Enhancement of cellular cAMP with dibutyryl cAMP abrogated LPS-mediated TNF-alpha expression in ethanol-treated cells. Importantly, cAMP did not affect LPS-inducible NF-kappaB activation but significantly decreased its transcriptional activity. Together, these data strongly suggest that ethanol can synergize with LPS to upregulate the induction of TNF gene expression and consequent TNF overproduction by decreasing the cellular cAMP levels in monocytes/macrophages. Furthermore, these data also support the notion that cAMP-elevating agents could constitute an effective therapeutic approach in attenuating or preventing the progression of liver disease in alcoholic patients.

Animals↗

PubMed2006

Interactions of cytokines, S-Adenosylmethionine, and S-Adenosylhomocysteine in alcohol-induced liver disease and immune suppression.

Alcoholic liver disease (ALD) remains a leading cause of death in the USA. Defining mechanisms for liver cell death in ALD in order to develop potential new agents for therapeutic intervention is a major focus of the authors' work. Abnormal cytokine metabolism is a major feature of ALD, and a thorough understanding of both mechanisms and interactions of cytokine overproduction and sensitization are critical to developing a possible treatment for ALD. S-Adenosylmethionine has been used in a variety of animal studies and clinical trials and has been reported to improve biochemical parameters of liver function. Last, immunosuppression associated with chronic alcohol abuse is an important predisposing factor to opportunistic infections and cancer. It is the authors' working hypothesis that alcohol consumption leads to chronic activation of the immune system.

Animals↗

PubMed2005

Decreased serum adiponectin: an early event in pediatric nonalcoholic fatty liver disease.

OBJECTIVE: To evaluate the relative concentrations of cytokines in pediatric nonalcoholic fatty liver disease (NAFLD). STUDY DESIGN: Thirty children were evaluated at a fasting morning visit to a pediatric research unit. RESULTS: Compared with normal-weight children (n = 12) and children who were overweight (n = 11), children who had presumed NAFLD (elevated Alanine aminotransferase [ALT] with negative work-up) (n = 7) had significantly lower mean serum adiponectin levels (P = .004). Adiponectin negatively correlated with body mass index (r = -0.60, P = .001), insulin (r = -0.74, P < .001), glucose (r = -0.52, P = .004), and ALT (r = -0.53, P = .003). There was no difference between normal-weight, obese, and presumed NAFLD subjects in mean serum tumor necrosis factor alpha and interleukin-6 and -8 concentrations nor in tumor necrosis factor alpha and interleukin-8 and -10 levels in an ex vivo lipopolysaccharide-stimulated system. CONCLUSIONS: Serum adiponectin is reduced in children with elevated ALT, similar to adults. However, children with presumed NAFLD do not have elevated pro-inflammatory cytokine levels. This suggests that depressed adiponectin plays a more proximal role than elevated levels of circulating pro-inflammatory cytokines in the development of NAFLD in children.

Adiponectin↗

PubMed2005

Dysregulated cytokine metabolism, altered hepatic methionine metabolism and proteasome dysfunction in alcoholic liver disease.

Alcoholic liver disease (ALD) remains an important complication and cause of morbidity and mortality from alcohol abuse. Major developments in our understanding of the mechanisms of ALD over the past decade are now being translated into new forms of therapy for this disease process which currently has no FDA approved treatment. Cytokines are low molecular weight mediators of cellular communication, and the pro-inflammatory cytokine tumor necrosis factor (TNF) has been shown to play a pivotal role in the development of experimental ALD. Similarly, TNF levels are elevated in the serum of alcoholic hepatitis patients. Abnormal methionine metabolism is well documented in patients with ALD, with patients having elevated serum methionine levels, but low S-adenosylmethionine levels in the liver. On the other hand, S-adenosylhomocysteine and homocysteine levels are elevated in ALD. Recent studies have documented potential interactions between homocysteine and S-adenosylhomocysteine with TNF in the development of ALD. Altered proteasome function also is now well documented in ALD, and decreased proteasome function can cause hepatocyte apoptosis. Recently it has been shown that decreased proteasome function can also act synergistically to enhance TNF hepatotoxicity. Hepatocytes dying of proteasome dysfunction release pro-inflammatory cytokines such as Interleukin-8 to cause sustained inflammation. This article reviews the interactions of cytokines, altered methionine metabolism, and proteasome dysfunction in the development of ALD.

Cytokines↗

PubMed2004

Advances in alcoholic liver disease.

Cytokines are mediators of cellular communication produced by multiple liver cell types. Cytokines can directly induce either necrosis or apoptosis. They can also recruit such cells as neutrophils and lymphocytes, which can mediate liver damage. Increased levels of hepatotoxic cytokines such as tumor necrosis factor-alpha are documented in alcoholic liver disease (ALD) and nonalcoholic steatohepatitis (NASH) and have been shown to play a mechanistic role in both of these disease processes. Transforming growth factor-beta is a profibrotic cytokine that is critical in hepatic fibrosis. Beneficial cytokines, such as interleukin (IL)-10 and -6, also exist. Such beneficial cytokines as adiponectin are made outside the liver and appear to protect against ALD and NASH. This article reviews the relevance of cytokines in human and experimental forms of liver injury, focusing on modulation of cytokines and the use of beneficial cytokines in treatment and prevention of liver injury in ALD, NASH, and hepatitis C.

Animals↗

PubMed2004

Eicosapentaenoic acid prevents LPS-induced TNF-alpha expression by preventing NF-kappaB activation.

BACKGROUND: Many studies have shown that fish oil supplementation inhibits tumor necrosis factor-alpha (TNF-alpha) production in mice and human subjects; however, the mechanisms remain unclear. Nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays an important role in controlling the expression of pro-inflammatory genes including TNF-alpha. Activation of NF-kappaB has been shown to mediate the maximal expression of TNF-alpha in human monocytes. NF-kappaB is kept in an inactive form in the cytoplasm by IkappaB, the inhibitory subunit of NF-kappaB complex. Phosphorylation and subsequent degradation of IkappaB lead to NF-kappaB activation. OBJECTIVES: The effect of eicosapentaenoic acid (EPA), a major n-3 fatty acid in fish oil, on the lipopolysaccharide (LPS)-induced expression of TNF-alpha and activation of NF-kappaB were investigated. The mechanism underlying EPA modulation of NF-kappaB activation was also studied. METHODS: Human monocytic THP-1 cells were pre-incubated with EPA and stimulated with LPS. The levels of secreted TNF-alpha were determined by ELISA. The DNA binding activity of NF-kappaB was analyzed by EMSA. The degradation and phosphorylation of IkappaB-alpha were examined by Western blot analysis. RESULTS: TNF-alpha production and expression induced by LPS were significantly decreased in cells pre-incubated with EPA. LPS-induced NF-kappaB activation, translocation of p65 subunit to the nucleus, phosphorylation and degradation of IkappaB-alpha were partially prevented by EPA. CONCLUSIONS: The results suggest that suppression of the TNF-alpha expression by EPA is partly attributed to its inhibitory effect on NF-kappaB activation. EPA appears to prevent NF-kappaB activation by preventing the phosphorylation of IkappaB-alpha.

Blotting, Western↗

PubMed2003

Inhibition of proteasome function leads to NF-kappaB-independent IL-8 expression in human hepatocytes.

Breakdown of cellular proteins is a highly regulated process, and the ubiquitin-proteasome pathway is the major proteolytic system in the cell. It regulates the levels of numerous proteins that control gene expression and cell division, as well as responses to stress and inflammation. Recent studies have reported abnormalities in proteasome function in alcoholic liver disease (ALD). Moreover, a direct relation has been reported between impaired proteasome function and oxidative stress in experimental models of ALD. Neutrophil infiltration is a hallmark of ALD, and activated neutrophils are thought to play a role in the pathology of ALD. As a potent neutrophil chemoattractant and activator, interleukin 8 (IL-8) likely plays a key mechanistic role in many forms of liver injury. In this study, we evaluated the effects of inhibition of proteasome function on expression and release of IL-8 by human fetal hepatocytes and hepatoma cells. Our data demonstrate that inhibition of proteasome function in hepatocytes leads to apoptotic cell death. Decreased hepatocyte survival coincides with enhanced expression of IL-8, both at the protein and the messenger RNA (mRNA) levels. This increase in IL-8 is independent of nuclear factor kappaB (NF-kappaB) activation and is associated with an increase in c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1) activity. In conclusion, hepatocytes dying because of inhibition of proteasome function produce massive quantities of the proinflammatory chemokine IL-8, possibly resulting in neutrophil infiltration, increased inflammation, and liver injury.

Acetylcysteine↗

PubMed2002

Mechanisms of alcohol-mediated CD4+ T lymphocyte death: relevance to HIV and HCV pathogenesis.

Clinical and experimental studies have demonstrated that excessive alcohol consumption can result in impairment of the immune system, and can impact several immune functions including immune tolerance and host defense against opportunistic infections, and development of certain tumors. Although multiple factors are involved in the effects of ethanol on the immune system, several studies implicate chronic activation of immune cells and impairment of thymus-derived lymphocytes (T lymphocytes). Helper CD4+ T lymphocytes are the central regulators of the immune system and depletion of these lymphocytes is a major contributing factor in ethanol-induced immune dysfunction and exacerbation of HIV and/or HCV pathogenesis. However, the mechanisms involved in the ethanol induced CD4+ T cell depletion have only recently begun to be elucidated. Our work demonstrates that exposure of human CD4+ T cells to physiologically relevant concentrations of ethanol leads to the (i) enhanced activation of TNFalpha-inducible NFkappaB, the transcriptional regulator of the Fas promoter and ii) increased susceptibility to Fas-and activation-induced apoptotic death via augmentation of caspase 3 activity. Work done by us, and others, on the effects of ethanol on CD4+ T cell function and survival strongly suggests that alcohol plays a significant role as a co-factor in HIV and/or HCV pathogenesis.

Animals↗

PubMed2002

Ethanol enhances activation-induced caspase-3 dependent cell death in T lymphocytes.

BACKGROUND: Clinical and experimental studies have shown that an important deleterious consequence of excessive alcohol consumption is immunosuppression, specifically, a depletion in the mature CD4+ T-cell population. A predominant mechanism involved in T-cell depletion is activation-induced cell death (AICD). Although it is well documented that ethanol intake can cause depletion of CD4+ T cells, the mechanism of how alcohol mediates its effects is unclear. METHODS: The results were based on data from three separate experiments presented as mean +/- standard deviation (SD). Jurkat CD4+ T cells and peripheral blood lymphocytes were treated with 25 mM of ethanol (12-18 hr), followed by stimulation with mitogens Conconavalin A (5 microg/ml) and Phytohemmaglutinin (1 microg/ml) or T-cell receptor ligation (anti-CD3 antibody (5 microg/ml)) for 6 hr, and then harvested for measurement. The apoptotic cell death markers measured include cell viability, Caspase-3-like activity, and DNA fragmentation. RESULTS: We demonstrate that alcohol pretreatment enhances AICD of Jurkat CD4+ T cells and peripheral blood lymphocytes upon activation by CD3-crosslinking or stimulation with Conconavalin A and Phytohemmaglutinin. Furthermore, we find that the ethanol-mediated enhancement of T cells to apoptosis involves increased activation of Caspase-3 and can be abrogated by treatment with a specific inhibitor of Caspase-3. CONCLUSIONS: Our data indicate that ethanol can sensitize CD4+ T cells to enhanced stimulation-induced Caspase-3 activation and to subsequent AICD. This is, perhaps, an important mechanism in alcohol-induced immunosuppression.

Caspase 3↗