Clinical relevance of caspase-1 activated cytokines in acute pancreatitis: high correlation of serum interleukin-18 with pancreatic necrosis and systemic complications.

OBJECTIVES: There is recent experimental evidence that caspase-1 activation plays an instrumental role in the pathomechanism of severe acute pancreatitis. Besides interleukin-1beta, interleukin-18, a recently described proinflammatory cytokine, is cleaved into its biologically active form by caspase-1 as well. Interleukin-18 is known to have potent properties concerning the activation of the Th1-lymphocyte subset via costimulation of interferon-gamma production. In contrast to interleukin-1beta, little is known about the clinical impact of interleukin-18 in the course of acute pancreatitis.
DESIGN: Cohort study comparing patients with mild and severe acute pancreatitis associated with local and systemic complications during the course of the disease.
SETTING: Surgical and anesthesiological intensive care unit as well as wards of the department of general surgery. PATIENTS: We included 68 patients with acute pancreatitis in the present study. In terms of local complications, pancreatic necrosis was present in 37 patients, of whom 21 developed pancreatic infections. Systemic complications included pulmonary, renal, or cardiocirculatory insufficiency and were observed in 40, 18, and 25 patients, respectively. Severe multiple-organ dysfunction syndrome involving all three organ systems occurred in 18 patients, all suffering from pancreatic necrosis.
INTERVENTIONS: Serum samples were collected over 14 consecutive days after study inclusion. Ascites or peripancreatic exudate was obtained by ultrasound-guided fine needle aspiration in 14 cases. Sera and local aspirates were stored at -70 degrees C until analysis. MEASUREMENTS AND
RESULTS: Interleukin-18 and interferon-gamma were measured by commercially available enzyme-linked immunosorbent assays. Interleukin-18 concentrations were significantly increased after the fourth day of disease onset until the end of the observation period in patients who developed pancreatic necrosis and systemic complications such as pulmonary, renal, and cardiocirculatory failure as well as severe multiple-organ dysfunction syndrome. However, no correlation was found between the development of pancreatic infections and interleukin-18 concentrations. In contrast with interleukin-18, interferon-gamma concentrations did not show any significant difference with respect to the presence or absence of either systemic or local complications. Local interleukin-18 concentrations in ascites or peripancreatic exudate were up to 20-fold higher than systemic concentrations, whereas interferon-gamma concentrations did not differ.
CONCLUSIONS: Serum interleukin-18 concentrations are significantly elevated in patients with acute pancreatitis complicated by pancreatic necrosis and remote organ failure. The present data suggest an important role of caspase-1 dependent cytokine activation in the pathomechanism of severe acute pancreatitis beyond the experimental setting. In this context, interleukin-18 may serve as a potential target for new therapeutic approaches.