Muneyuki Shibata

Relationship between plasma cytokine concentration and multiple organ failure in patients with acute pancreatitis.

The dynamic aspects of circulating cytokines and cytokine modulators and their relationship with development of multiple organ failure (MOF) in patients with acute pancreatitis were analyzed. All cytokine and C-reactive protein levels in the circulation were higher than those in the MOF group. In particular, plasma concentrations of soluble tumor necrosis factor receptors (sTNF-RI and sTNF-RII) were significantly higher in patients with MOF than in those without even at admission. Furthermore, plasma concentrations of sTNF-Rs and interleukin-1 (IL-1) receptor antagonist (IL-1ra) were much higher than those of their counterparts, TNF-&agr; and IL-1&bgr;, respectively. These results suggest that the plasma concentrations of sTNF-Rs are useful predictors for the development of MOF, and actions of TNF-&agr; and IL-1&bgr; could be regulated by their modulators (soluble receptor and receptor antagonist, respectively) in the pathologic condition of severe acute pancreatitis.

Altered Cytokine Response in Rat Acute Pancreatitis Complicated with Endotoxemia

We demonstrated that the dynamic aspects of cytokine production in rat acute pancreatitis, which was induced by cerulein and aggravated by subsequent lipopolysaccharide (LPS) injection. A priming effect by induction of mild pancreatitis with cerulein enhanced the subsequent cytokine production by LPS injection. Alternatively, after induction of severe pancreatitis with cerulein and LPS, cytokine production was markedly suppressed for ≥90 hours. Production of interleukin-2 (IL-2) by splenocytes decreased, and mortality rate after cecal ligation and puncture (CLP) increased significantly after induction of severe acute pancreatitis. These results suggest that the suppression of a cytokine response in severe acute pancreatitis may alter the defense system and, as a result, increase mortality after CLP.

Tumor Necrosis Factor α Acts on Cultured Human Vascular Endothelial Cells to Increase the Adhesion of Pancreatic Cancer Cells

We studied the effect of tumor necrosis factor a (TNFa), one of the major inflammatory cytokines, on the adhesive reaction of pancreatic cancer cells to human umbilical vein endothelial cells (HUVECs) and on the hepatic metastasis of cancer cells in vivo. After TNFa stimulation, the expression of E-selectin, an adhesion molecule to neutrophils on HUVECs, increased. In addition, the adhesion of pancreatic cancer cells to HUVECs increased after TNFa stimulation, as was observed with neutrophils. The TNFa-induced adhesive response depended on the extent of sialyl Lewis a expression on cancer cells. The hepatic metastasis in vivo was often observed when cancer cells expressing a high amount of sialyl Lewis a were inoculated intrasplenically after increase in plasma TNFa concentration by lipopolysaccharide administration. Because sialyl Lewis a on cancer cells is a ligand for E-selectin on HUVECs, as sialyl Lewis x on neutrophils, TNFa upregulated the adhesive interaction between sialyl Lewis a on cancer cells and E-selectin on HUVECs. These results suggest that production of TNFa after surgical trauma may stimulate the hematogenic metastasis of cancer cells with a high sialyl Lewis a expression.

Hepatic injury induced by interleukin-18 administration: importance of preceding priming effect.

The priming effects of obstructive jaundice by bile duct ligation on interleukin (IL)-18-induced hepatic injury are investigated. The production of IL-12 and tumor necrosis factor-&agr; increased 3 days after bile duct ligation. Subsequent IL-18 injection to rats with obstructive jaundice caused by BDL resulted in prominent interferon-&ggr; production and hepatic injury. These results suggest that IL-18 with IL-12 and/or tumor necrosis factor-&agr; have synergistic effects on the induction of hepatic injury via interferon-&ggr; production on this model.

Increased concentrations of plasma interleukin-18 in patients with hepatic failure 1 week after surgery.

We investigated the dynamic aspects of circulatory interleukin (IL)-18 in patients who underwent a hepatectomy. In patients with hepatic failure after surgery, plasma concentrations of IL-6 and IL-10 increased in the early phase; however, the plasma concentrations of IL-18 increased in the later phase after 1 week. Interestingly, the increase in the plasma IL-18 concentration was correlated with that in serum bilirubin levels in hepatectomized patients. Hence, the decrease in the hepatic metabolism of IL-18 may cause the plasma accumulation of IL-18. This mechanism was confirmed using rat experiments. Intravenously administrated human IL-18 was excreted in bile. Furthermore, the plasma clearance of human IL-18 was prolonged in bile-duct-ligated rats. These results suggest that IL-18 is metabolized in the liver and excreted in bile, and an increase in plasma IL-18 in patients with hepatic failure reflects the decreased metabolism in the liver.

Contribution of IL-18 and its related cytokines on the development of hepatic dysfunction in non-biliary acute pancreatitis

Abstract Background : Interleukin-18 (IL-18) production is the main mechanism of hepatic injury in several animal models via further gamma interferon (IFN-γ) release. IL-18 also functions as an inducer of proinflammatory cytokines as TNF-α, which are also shown to induce organ injuries in many severe inflammatory conditions. To clarify the mechanism of hepatic injury developed in acute pancreatitis, plasma concentrations of IL-18 and its related cytokines were analyzed. Patients and methods : Plasma levels of IL-18, IL-12, IFN-γ, TNF-α, soluble TNF receptor (sTNF-R) and soluble Fas ligand (sFas-L) were measured by ELISA. Results : Plasma concentrations of IL-18 in patients with hepatic injury increased during the first few days apparently and remained so to some extent thereafter. However, IFN-γ showed no apparent increase in plasma concentrations. Those of TNF-α and sTNF-R remained increased in the hepatic injury group. Conclusion : These results suggest that IL-18 may act as a pro-inflammatory cytokine, which provokes the cytokine storm and eventually hepatic injury.

Increase in plasma IL-18 in patients with hepatic failure reflects the decreased hepatic metabolism

Abstract Hepatectomy is one of the most effective means of managing hepatic neoplasms. However, some patients are still susceptible to hepatic failure after the procedure. In patients with hepatic failure after surgery, plasma concentrations of IL-18 increased gradually after 1 week. Interestingly, the increase in the plasma IL-18 correlated with that in serum bilirubin. Because IL-18 is metabolized in the liver and excreted in bile, the increase in plasma IL-18 in patients with hepatic failure reflects the decreased metabolism in the liver.