Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat

Nanji, Amin A.; Jokelainen, Kalle; Rahemtulla, Amir; Miao, Lili; Fogt, Franz; Matsumoto, Hiroshi; Tahan, Steven R.; Su, Grace L.

doi:10.1002/hep.510300402

Cited by 201 publications

(140 citation statements)

References 59 publications

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“…28 NF-B binding activity is stronger in the livers of rats chronically exposed to ethanol by gastric infusion than in controls, a response that is thought to occur in Kupffer cells. 29 Gutderived LPS activation of Kupffer cells leads to NFBdependent synthesis of cytokines and chemokines. Ethanol also activates the transcription factor AP-1.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid-induced leucine zipper: A key protein in the sensitization of monocytes to lipopolysaccharide in alcoholic hepatitis

et al. 2007

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Glucocorticoid-induced leucine zipper (GILZ), a recently identified protein induced by glucocorticoids (GCs), inhibits the nuclear factor B pathway and the activation of monocytes/macrophages by lipopolysaccharides (LPS). This study aimed to elucidate the contribution of GILZ to the pathogenesis of alcoholic hepatitis (AH): we (1) assessed GILZ expression in the livers of patients with AH and (2) treated patients with severe AH with GCs (prednisolone 40 mg/day) and studied the effect of GILZ modulation on circulating monocyte function. We quantified GILZ expression in the livers of 42 consecutive alcoholic patients (21 with and 21 without AH). GILZ messenger RNA (mRNA) levels were lower in the livers of patients with AH versus those without AH (P < 0.05). We collected circulating monocytes from patients with severe AH before and 48 hours after GC treatment to quantify GILZ expression and cytokine secretion. GC treatment induced significantly higher levels of GILZ mRNA than that observed before treatment and impaired LPS-induced tumor necrosis factor-␣ (TNF-␣) and regulated upon activation, normal T cell-expressed secretion (RANTES) by these monocytes. We transfected circulating monocytes with GILZ small interfering RNA (siRNA), specifically blocking GILZ expression, to demonstrate the role of GILZ in mediating GC effect. GILZ siRNA abrogated the effect of GC treatment on LPS-induced TNF-␣ and RANTES secretion. Conclusion: Low expression of GILZ may contribute to liver inflammation in AH. GCs enhance GILZ expression, abrogating macrophage sensitivity to LPS and proinflammatory cytokine secretion. These findings may explain the beneficial effect of GC treatment in patients with severe AH. (HEPATOLOGY

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Section: Discussionmentioning

confidence: 99%

Glucocorticoid-induced leucine zipper: A key protein in the sensitization of monocytes to lipopolysaccharide in alcoholic hepatitis

et al. 2007

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“…injected mice. Even though the proinflammatory role of MIP-2 has not been explored in murine models of malaria, increased hepatic N accumulation has been reported in mice following systemic administration of high doses of MIP-2 (46), and immunoneutralization of MIP-2 was shown to decrease N influx into the liver and reduce hepatic injury (47). In light of these studies, it is conceivable that by increasing MIP-2 expression, HZ could contribute to favor peripheral N recruitment and subsequent liver injury.…”

Section: Discussionmentioning

confidence: 99%

Hemozoin-Inducible Proinflammatory Events In Vivo: Potential Role in Malaria Infection

Jaramillo

Plante

Ouellet

et al. 2004

The Journal of Immunology

123

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During malaria infection, high levels of proinflammatory molecules (e.g., cytokines, chemokines) correlate with disease severity. Even if their role as activators of the host immune response has been studied, the direct contribution of hemozoin (HZ), a parasite metabolite, to such a strong induction is not fully understood. Previous in vitro studies demonstrated that both Plasmodium falciparum HZ and synthetic HZ (sHZ), β-hematin, induce macrophage/monocyte chemokine and proinflammatory cytokine secretion. In the present study, we investigated the proinflammatory properties of sHZ in vivo. To this end, increasing doses of sHZ were injected either i.v. or into an air pouch generated on the dorsum of BALB/c mice over a 24-h period. Our results showed that sHZ is a strong modulator of leukocyte recruitment and more specifically of neutrophil and monocyte populations. In addition, evaluation of chemokine and cytokine mRNA and protein expression revealed that sHZ induces the expression of chemokines, macrophage-inflammatory protein (MIP)-1α/CCL3, MIP-1β/CCL4, MIP-2/CXCL2, and monocyte chemoattractant protein-1/CCL2; chemokine receptors, CCR1, CCR2, CCR5, CXCR2, and CXCR4; cytokines, IL-1β and IL-6; and myeloid-related proteins, S100A8, S100A9, and S100A8/A9, in the air pouch exudates. Of interest, chemokine and cytokine mRNA up-regulation were also detected in the liver of i.v. sHZ-injected mice. In conclusion, our study demonstrates that sHZ is a potent proinflammatory agent in vivo, which could contribute to the immunopathology related to malaria.

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“…For instance, the transcription factor NF-κB is redox-sensitive and plays an important role in signaling (34). Since both alcohol and the peroxisome proliferator WY-14,643 activate NF-κB nearly exclusively in Kupffer cells in the rat (35), it was hypothesized that NF-κB is involved in alcohol-induced liver injury by stimulating TNF-α production in Kupffer cells. In wild-type mice fed a highfat control diet for 4 weeks, NF-κB activity was minimal; however, activity was increased significantly, about twofold, by enteral ethanol in wild-type mice (Figure 3, a and b).…”

Section: Figurementioning

confidence: 99%

NADPH oxidase–derived free radicals are key oxidants in alcohol-induced liver disease

Kono¹,

Rusyn²,

Yin³

et al. 2000

J. Clin. Invest.

459

337

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Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat

Abstract: Alcoholic liver injury is a complex process involving several injury mechanisms and multiple cellular targets. 1

Cited by 201 publications

References 59 publications

Glucocorticoid-induced leucine zipper: A key protein in the sensitization of monocytes to lipopolysaccharide in alcoholic hepatitis

Glucocorticoid-induced leucine zipper: A key protein in the sensitization of monocytes to lipopolysaccharide in alcoholic hepatitis

Hemozoin-Inducible Proinflammatory Events In Vivo: Potential Role in Malaria Infection

NADPH oxidase–derived free radicals are key oxidants in alcohol-induced liver disease

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