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2001 Abstract: 1796 Elastase-Induced Kupffer Cell Cytokine Production Is Downregulated by Gadolinium via NF-?B but not P38 MAP Kinase

2001 Digestive Disease Week

# 1796 Elastase-Induced Kupffer Cell Cytokine Production Is Downregulated by Gadolinium via NF-?B but not P38 MAP Kinase
Jun Yang, Colleen Jaffray, James G. Norman, Michel M. Murr, Tampa, FL

BACKGROUND: Kupffer cells (KC) are an important source of proinflammatory cytokines in sepsis. We have recently demonstrated that pancreatic elastase induces hepatic TNF production from KC and a pattern of liver injury similar to that seen during acute pancreatitis. AIM: To determine the role of second-messenger systems in elastase-induced cytokine production by KC and the mechanisms by which Gadolinium (Gd) modulates KC cytokine production.

METHODS: Tissue cultures of freshly isolated rat KC were treated with elastase (1U/ml) ± Gd (0.5 mg/ml) to inhibit KC function, PDTC (0.5 mg/ml) to inhibit NF-kB, or CNI-1493 (1mM) to inhibit P38 MAPK phosphorylation. TNF protein (ELISA), mRNA (RT-PCR), NF-kB activation (EMSA) and phosphorylated P38 MAPK (western blot) were determined. Data are mean ± SEM.

RESULTS: Elastase induced massive TNF production compared to controls (696±22 vs 20±2 pg/ml, p<0.001) and upregulated TNF mRNA, NF-kB activation and P38 MAPK phosphorylation (Figure). PDTC and CNI-1493 diminished elastase-induced TNF production (28±2 and 37±8 pg/ml, respectively, p<0.001 vs elastase). Gd diminished the elastase-induced TNF production in a dose dependent manner (data not shown) without affecting the viability of KC. Gd attenuated elastase-induced overexpression of mRNA and activation of NF-kB but did not affect phosphorylation of P38 MAPK (Figure).

CONCLUSION: Pancreatic elastase activates KC TNF production via NF-kB and P38 MAPK. Gd pretreatment attenuates elastase-induced KC TNF production by inhibiting activation of NF-kB but not through P38 MAPK phosphorylation. NF-kB and P38 MAPK may act as independent pathways for cytokine production by KC during pancreatitis.

Support: VA Merit Review Award (JN), Surgery Seed Grant (MM)

Society for Surgery of the Alimentary Tract

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