Absence of endogenous interleukin-6 enhances the inflammatory response during acute pancreatitis induced by cerulein in mice.
Interleukin-6 (IL-6) exerts a wide spectrum of regulatory activities during immune and inflammatory responses. The aim of this study was to investigate the role of endogenous IL-6 in the inflammatory response associated with acute pancreatitis. Acute pancreatitis was induced by hourly (x5) i.p. injections of cerulein (50 microg/kg, suspended in saline solution) in IL-6 deficient mice (IL-6-KO) and wild-type (IL-6WT) littermates. IL-6KO mice exhibited a more severe tissue injury and a higher rate of mortality and when compared to IL-6WT mice. Acute pancreatitis was characterized by edema, neutrophil infiltration, tissue hemorrhage and cell necrosis, upregulation of P-selectin and intercellular adhesion molecule-1 (ICAM-1), as well as increases in the serum levels of amylase and lipase. The degree of oxidative and nitrosative tissue damage was significantly greater in IL-6KO mice than in wild-type littermates, as indicated by higher tissue levels of malondialdehyde and nitrosylated proteins. Plasma levels of the inflammatory cytokines tumour necrosis factor-alpha and interleukin-1beta were also greatly enhanced in IL-6KO mice when compared to wild-type mice. These events were correlated with an increase in the staining (immunoreactivity) for poly (ADP-ribose) polymerase (PARP) in the pancreas of cerulein-treated IL-6WT. The staining for PARP was more pronounced in IL-6KO mice subjected to acute pancreatitis than in the corresponding WT mice. These data demonstrate that endogenous IL-6 exerts an anti-inflammatory role during acute pancreatitis, possibly by regulating the expression of adhesion molecules, the subsequent adhesion and activation of neutrophils and finally the generation of cytokine and reactive oxygen or nitrogen species.
Cuzzocrea
Salvatore
S
Institute of Pharmacology, School of Medicine, University of Messina, Italy. salvator@www.unime.it
Mazzon
Emanuela
E
Dugo
Laura
L
Centorrino
Tommaso
T
Ciccolo
Antonio
A
McDonald
Michelle C
MC
de Sarro
Agelina
A
Caputi
Achille P
AP
Thiemermann
Christoph
C
D000681:Amylases / Q000097:blood; D000818:Animals; D002108:Ceruletide / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D008049:Lipase / Q000097:blood; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D019007:P-Selectin / Q000097:blood; D010179:Pancreas / Q000276:immunology / Q000378:metabolism; D010195:Pancreatitis / Q000276:immunology*; D009195:Peroxidase / Q000378:metabolism; D010641:Phenotype; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D007375:Interleukin-1; D015850:Interleukin-6; D019007:P-Selectin; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C002744:3-nitrotyrosine; D014443:Tyrosine; D002108:Ceruletide; D009195:Peroxidase; D011065:Poly(ADP-ribose) Polymerases; D008049:Lipase; D000681:Amylases