INTRAPANCREATIC INTERLEUKIN-1-BETA GENE-EXPRESSION BY SPECIFIC LEUKOCYTE POPULATIONS DURING ACUTE-PANCREATITIS

The importance of interleukin-1 beta (IL-1 beta) in the pathogenesis o f acute pancreatitis has been demonstrated by dramatic attenuation of pancreatic destruction and significant increases in survival when its actions are inhibited. The pancreas has been shown to be a major produ cer of IL-1 beta during pancreatitis but the cell(s) of origin remains unknown. Hypothesizing that infiltrating leukocytes contribute substa ntially, the intrapancreatic production of IL-1 beta was examined afte r specific leukocyte populations were manipulated in vivo prior to the induction of pancreatitis. Sixty-four adult male Swiss mice were assi gned to one of four groups 48 hr prior to induction of pancreatitis: ( 1) PMN depletion via anti-murine PMN antiserum [PMN-d], (2) macrophage (M phi) depletion via anti-macrophage antiserum [M phi-d], (3) PMN an d M phi depletion [PMN+M phi-d], and (4) Immunocompetent Pancreatitis. Edematous pancreatitis was induced in all experimental groups by caer ulein (50 mu g/kg/hr ip x 4). Animals were sacrificed 6 hr after induc tion of pancreatitis with severity determined by blind histologic grad ing and serum amylase, lipase, and interleukin-6 (IL-6) levels. Intrap ancreatic IL-1 beta production was determined by immunohistochemistry and semiquantitative differential RT-PCR. Pancreatitis developed in al l animals receiving caerulein; however, leukocyte-depleted animals sho wed significantly attenuated levels of serum amylase, lipase, and IL-6 , as well as lower histologic severity scores. Similarly, pancreatitis induction in immunocompetent mice showed pancreatic infiltration of I L-1 beta-producing cells, whereas the leukocyte-depleted animals had s ignificantly decreased numbers (PMN+M phi-d < M phi-d < PMN-d). IL-1 b eta mRNA was upregulated in all animals developing pancreatitis with s ignificantly lower levels seen in the leukocyte-depleted groups. We co nclude that infiltrating leukocytes, both neutrophils and macrophages, are responsible for the majority of intrapancreatic IL-1 beta product ion during acute pancreatitis. The elimination of leukocytes and their products, including IL-1 beta, significantly decreases the severity o f pancreatic destruction. (C) 1996 Academic Press, Inc.