Influence of Kupffer cells on hepatic signal transduction as demonstrated by second messengers and nuclear transcription factors

Abstract

AIM:To understand the influence of Kupffer cell (KC) on signal transduction pathways in the liver. METHODS:To decrease selectively the number and function of KC, Kunming mice were ip injected with a single dose of gadolinium chloride (GdCl 3 , 20 mg·kg -1 ), the time-effect relationship assessment was performed after 1 d, 3 d and 6 d. sALT, sGST, liver glycogen content, phagocytic index, and expression of CD68 were assessed as the indexes of hepatotoxicity and functions of KC respectively, and morphology of KC was observed with transmission electron microscopy. Furthermore, cAMP, PGE 2 level, nitric oxide(NO) content, and mRNA expression of NFkappaBp65, Erk1, STAT1 were examined. RESULTS:GdCl 3 could selectively cause apoptosis of KC and obvious reduction of KC's activity, but no hepatotoxicity was observed. One day after KC blockade, NO, PGE 2 , cAMP contents in the liver were reduced 21.0 %, 6.94-fold, 8.3 %, respectively, and mRNA expression of NFkappaBp65 was decreased 3.0-fold. The change tendency of NO, PGE 2 , and cAMP contents and mRNA expression of NFkappaBp65 were concomitant with recovery of the functions of KC. The contents of NO, PEG2, cAMP were increased when the functions of KC was recovered. However, all of the changes could not return to the normal level except NO content after 6 d Gdcl 3 treatment. No obvious changes were found in STAT1 and Erk1 mRNA expression in the present study.

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

“…Detrimental effects of Kupffer cells are attributed to production of ROS, which challenges the oxidative stress defense of cellular neighbors (Jaeschke and Farhood, 1991), as well as to release of pro-inflammatory cytokines, which by activation of hepatocellular receptors (i.e., IL-6 receptor, TNF-␣ receptors R1 and R2) induce specific hepatocellular programs, such as signal transducer and activator of transcription-3 and NF-〉 signaling and/or apoptosis (Ding et al, 2003;Kresse et al, 2005;Bilzer et al, 2006;Yu et al, 2006). By recruitment of adaptor proteins such as TRADD, TRAF2, RIP, and FADD, TNF receptors activate NF-〉, JNK, and p38 and promote apoptosis by activation of caspases, mitochondrial depolarization, and subsequent release of cytochrome c (Schwabe and Brenner, 2006).…”

Chlorogenic Acid Protects against Advanced Alcoholic Steatohepatitis in Rats via Modulation of Redox Homeostasis, Inflammation, and Lipogenesis

“…Kupffer cells are centrally involved in regulation of the NF-κB pathway and hepatic inflammatory response. Inactivation of Kupffer cells with gadolinium chloride resulted in a decrease of NF-κB DNA binding activity [62] and the mRNA expression of NF-κB [63], which prevents the development of alcoholic steatosis [64] and confirms that the TLR4/NF-κB signaling pathway can trigger lipid metabolism in ALD. Moreover, TNFα, a proinflammatory cytokine that is controlled by the TLR4/NF-κB pathway, increases fat deposition in the liver, thus upregulates SREBP1 gene expression [63][64][65][66].…”

“…Inactivation of Kupffer cells with gadolinium chloride resulted in a decrease of NF-κB DNA binding activity [62] and the mRNA expression of NF-κB [63], which prevents the development of alcoholic steatosis [64] and confirms that the TLR4/NF-κB signaling pathway can trigger lipid metabolism in ALD. Moreover, TNFα, a proinflammatory cytokine that is controlled by the TLR4/NF-κB pathway, increases fat deposition in the liver, thus upregulates SREBP1 gene expression [63][64][65][66]. Consequently, we showed that in the liver of rats with chronic alcohol intoxication, CGA attenuated steatosis by decreasing the mRNA expression of the lipogenic genes, Srebp1 and Acc.…”