PMID: 18336664 Endotoxin/lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, is an important activator of Kupffer cells, stimulating the production of inflammatory and fibrogeniccytokines, as well as reactive oxygen species (ROS). PMID: 18336664, 9756487 One working model for the progression of alcoholic liver disease proposes that increased exposure of Kupffer cells to LPS during chronic ethanol consumption contributes to increased production of inflammatory mediators, in particular tumor necrosis factor TNF-alpha and ROS, leading to the progression of fatty liver, inflammation and fibrosis.

PMID: 18336664 IL-10 expression is induced by various inflammatory mediators, such as LPS and TNF-alpha. PMID: 18336664, 17537727 Interestingly, we found that initially adiponectin increases the production of TNF-alpha by RAW 264.7 macrophages; this TNF-alpha, in the continued presence of adiponectin, then increases production of IL-10.

PMID: 18336664, 1940369, 1940799, 8386517 IL-10 then acts to limit excessive production of pro-inflammatory cytokines, including TNF-alpha and IL-1b by decreasing cytokine gene transcription, as well as regulating the stability and/or translation of target mRNAs. PMID: 18336664, 17537727 Treatment of RAW 264.7 macrophages with adiponectin increases the expression of IL-10 mRNA and peptide. PMID: 18336664, 17537727 Interestingly, we found that initially adiponectin increases the production of TNF-alpha by RAW 264.7 macrophages; this TNF-alpha, in the continued presence of adiponectin, then increases production of IL-10.

PMID: 18336664, 1940369, 1940799, 8386517 IL-10 then acts to limit excessive production of pro-inflammatory cytokines, including TNF-alpha and IL-1b by decreasing cytokine gene transcription, as well as regulating the stability and/or translation of target mRNAs.

PMID: 18336664, 15369797, 17537727 While the mechanisms for the long-term anti-inflammatory effects of adiponectin are not well understood, recent data suggest that adiponectin acts, at least in part, to increase the expression of anti-inflammatory mediators, such as interleukin (IL)-10. PMID: 18336664, 17537727 Treatment of RAW 264.7 macrophages with adiponectin increases the expression of IL-10 mRNA and peptide.

PMID: 18336664, 17537727 Interestingly, we found that initially adiponectin increases the production of TNF-alpha by RAW 264.7 macrophages; this TNF-alpha, in the continued presence of adiponectin, then increases production of IL-10. PMID: 18336664 This initial gAcrp-mediated increase in TNF-alpha production by macrophages was mediated via activation of ERK1/2¢ªEgr-1 and nuclear factor (NF)-kappaB-dependent mechanisms.

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter.

PMID: 18336664 Endotoxin/lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, is an important activator of Kupffer cells, stimulating the production of inflammatory and fibrogeniccytokines, as well as reactive oxygen species (ROS). PMID: 18336664, 16410364, 10961870, 15033490 Adiponectin suppresses phagocytic activity, as well as lipopolysaccharide (LPS)- stimulated cytokine production in macrophages.

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter. PMID: 18336664 gAcrp-stimulated IL-10 expression was also dependent on the phosphorylation of cAMP response element-binding protein and the cAMP response element in the IL-10 promoter.

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter (Park, et al., unpubl. obs, 2007); and (ii) an NF-kappaB and Egr-1 pathway, leading to increased production of TNF-alpha.

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter (Park, et al., unpubl. obs, 2007); and (ii) an NF-kappaB and Egr-1 pathway, leading to increased production of TNF-alpha.

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter (Park, et al., unpubl. obs, 2007); and (ii) an NF-kappaB and Egr-1 pathway, leading to increased production of TNF-alpha. PMID: 18336664 This initial gAcrp-mediated increase in TNF-alpha production by macrophages was mediated via activation of ERK1/2¢ªEgr-1 and nuclear factor (NF)-kappaB-dependent mechanisms.

PMID: 18336664 We next identified two parallel signaling pathways required for adiponectin-stimulated IL-10 transcription: (i) an ERK1/2- and protein kinase A (PKA)-dependent increase in cAMP response element-binding protein (CREB) phosphorylation which acted via the CRE in the IL-10 promoter (Park, et al., unpubl. obs, 2007); and (ii) an NF-kappaB and Egr-1 pathway, leading to increased production of TNF-alpha. PMID: 18336664 This initial gAcrp-mediated increase in TNF-alpha production by macrophages was mediated via activation of ERK1/2¢ªEgr-1 and nuclear factor (NF)-kappaB-dependent mechanisms.

PMID: 18336664, 9756487 One working model for the progression of alcoholic liver disease proposes that increased exposure of Kupffer cells to LPS during chronic ethanol consumption contributes to increased production of inflammatory mediators, in particular tumor necrosis factor TNF-alpha and ROS, leading to the progression of fatty liver, inflammation and fibrosis. PMID: 18336664, 1940369, 1940799, 8386517 IL-10 then acts to limit excessive production of pro-inflammatory cytokines, including TNF-alpha and IL-1b by decreasing cytokine gene transcription, as well as regulating the stability and/or translation of target mRNAs. PMID: 18336664 Increased IL-10 expression was ultimately required for the suppression of TLR4-mediated signaling by gAcrp.

PMID: 18336664, 12840063 Importantly, treatment of mice with adiponectin during chronic ethanol exposure prevents the development of ethanol-induced liver injury,26 in part by increasing fatty acid oxidation in the liver, thus preventing ethanol-induced steatosis, as well as decreasing TNF-alpha expression.

PMID: 18336664, 12840063 Importantly, treatment of mice with adiponectin during chronic ethanol exposure prevents the development of ethanol-induced liver injury,26 in part by increasing fatty acid oxidation in the liver, thus preventing ethanol-induced steatosis, as well as decreasing TNF-alpha expression. PMID: 18336664, 16410364 Importantly, overnight treatment of Kupffer cells with adiponectin can normalize the chronic ethanol-induced sensitization of LPS-stimulated TNF-alpha expression, normalizing the increased production of ROS, as well as ERK1/2 and p38 phosphorylation.

PMID: 18336664, 16410364, 15033490, 16325814 In particular, LPS-stimulated NK-kappaB and ERK1/2 activation are sensitive to the inhibitory effects of adiponectin.

PMID: 18336664, 16410364, 15033490, 16325814 In particular, LPS-stimulated NK-kappaB and ERK1/2 activation are sensitive to the inhibitory effects of adiponectin. PMID: 18336664, 16410364 Importantly, overnight treatment of Kupffer cells with adiponectin can normalize the chronic ethanol-induced sensitization of LPS-stimulated TNF-alpha expression, normalizing the increased production of ROS, as well as ERK1/2 and p38 phosphorylation.

PMID: 18336664, 16410364 Importantly, overnight treatment of Kupffer cells with adiponectin can normalize the chronic ethanol-induced sensitization of LPS-stimulated TNF-alpha expression, normalizing the increased production of ROS, as well as ERK1/2 and p38 phosphorylation.

PMID: 18336664 IL-10 expression is induced by various inflammatory mediators, such as LPS and TNF-alpha.