Smith, B.W., Hebbard, L., and George, J. (2009) Adiponectin induces pro-inflammatory cytokines in kupffer cells and tolerance to itself via the generation of IL-10. Journal of Gastroenterology and Hepatology, 24 (Suppl. 2). A274-A274.

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Abstract

Exogenous adiponectin (Acrp) reduces the severity of CCl4-induced liver fibrosis and has been shown to abrogate LPS-induced cytokine release by Kupffer cells (KC). However, Acrp also directly stimulates pro-inflammatory and pro-fibrotic cytokine release by KCs. The mechanism for Acrp-induced pro-inflammatory responses in KCs has not been adequately defined. We sought to characterise the mechanisms which underlie the pro-inflammatory effects of Acrp.

Methods Day 2 primary rat KCs were treated with 1 mg/ml full length Acrp (flAcrp) for 4 h. The induction of KC tolerance to adiponectin was examined by priming KCs with flAcrp for 18 h and subsequent re-treatment for 4 h. To test for the presence of an IL-10 autocrine loop, 5 mg/ml soluble anti-rat IL-10 antibody or 20 ng/ml recombinant rat IL-10 was applied in conjunction with flAcrp treatment for 4 h. We determined the relative expression of cytokines using real-time qPCR. To ascertain if any Acrp signal transduction pathways in KC were affected, we performed a time course study and examined for phospho-protein changes through Western Blot analysis.

Results IL-10 mRNA was increased 68-fold following flAcrp treatment for 4 h. flAcrp induced TNFa mRNA 202-fold, TGFb mRNA 2-fold and IL-6 mRNA 20-fold, while PDGF mRNA remained unchanged when compared to control KCs. Priming KC for 18 h with flAcrp prior to treat- ment abrogated this up-regulation. TNFa mRNA decreased 2.5-fold (p < 0.05), TGFb mRNA deceased 5-fold (p < 0.005), PDGF mRNA decreased 4-fold (p < 0.005) and IL-6 mRNA decreased 5-fold (p < 0.005) compared to non-Acrp-primed KCs. Inflammatory cytokine up-regulation in 4 h Acrp treated KCs was overturned in KCs treated with flAcrp and exogenous IL-10 peptide. Conversely, IL-10 antibody prevented inflammatory cytokine down-regulation in Acrp-primed KCs. No change in Acrp signal transduction was recorded after Acrp-priming. We postulate that IL-10 synthesised during the priming period modulates the cytokine down-regulation in tolerized cells.

Conclusions These observations suggest that Acrp mediates acute inflammatory responses in KCs that are down-regulated by IL-10. These pro-inflammatory effects may be important in mediating liver injury in conditions associated with rapid and massive weight loss.

Item ID:	86235
Item Type:	Article (UNSPECIFIED)
ISSN:	1440-1746
Copyright Information:	© 2009 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
Date Deposited:	22 Jul 2025 01:22
FoR Codes:	32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320209 Gastroenterology and hepatology @ 100%
SEO Codes:	20 HEALTH > 2001 Clinical health > 200101 Diagnosis of human diseases and conditions @ 100%
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