ABSENCE OF ENDOGENOUS INTERLEUKIN-6 ENHANCES THE INFLAMMATORY RESPONSE DURING ACUTE PANCREATITIS INDUCED BY CERULEIN IN MICE

doi:10.1006/cyto.2002.0883

Cytokine

Volume 18, Issue 5, June 2002, Pages 274-285

https://doi.org/10.1006/cyto.2002.0883 Get rights and content

Abstract

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 (×5) i.p. injections of cerulein (50 μg/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-α and interleukin-1β 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.

References (60)

AM Kusske et al.
Cytokines and acute pancreatitis
Gastroenterology
(1996)
HG Beger et al.
Bacterial contamination of pancreatic necrosis: a prospective clinical study
Gastroenterology
(1986)
T Grady et al.
Chemokine gene expression in rat pancreatic acinar cells is an early event associated with acute pancreatitis
Gastroenterology
(1997)
T Hirano
Interleukin-6 and its relation to inflammation and disease
Clin Immunol Immunopathol
(1992)
T Alonzi et al.
Impaired stat3 activation following localized inflammatory stimulus in IL-6 deficient mice
Cytokine
(1998)
M Romano et al.
Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment
Immunity
(1997)
H Tilg et al.
IL-6 and APPs: anti-inflammatory and immunosuppressive mediators
Immunology
(1997)
C Niederau et al.
Caerulein-induced acute necrotizing pancreatitis in mice: protective effects of proglumide, benzotript, and secretin
Gastroenterology
(1985)
KM Mullane et al.
Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into ischemic myocardium
J Pharmacol Meth
(1985)
H. Ohkawa et al.
Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction
Anal Biochem
(1979)

R Luthen et al.

Beneficial effects of L-2–oxothiazolidine-4–carboxylate on cerulein pancreatitis in mice

Gastrenterology

(1997)

AJ Rongione

Interleukin 10 reduces the severity of acute pancreatitis in rats

Gastroenterolgy

(1997)

H Rubbo

Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. Formation of novel nitrogen-containing oxidized lipid derivatives

J Biol Chem

(1994)

C Szabo et al.

Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion

Trends Pharmacol Sci

(1998)

EL Bradley

A clinically based classification system for acute pancreatitis: summary of the international Symposium on Acute Pancreatitis, Atlanta GA, September 11 through 13, 1992

Arch Surg

(1993)

Crit Care Med

(1993)

H Rinderknecht

Fatal panreatitis: a consequence of excessive leukocyte stimulation?

Int J Pancreatol

(1988)

JE Dominguez-Munoz et al.

Monitoring of serum proteinase-antiproteinase balance and systemic inflammatory response in prognostic evaluation of acute pancreatitis: results of a prospective multicenter study

Dig Dis Sci

(1993)

LJ Formela et al.

Inflammatory mediators in acute pancreatitis

Br J Surg

(1995)

J Scholmerich

Interleukins in acute pancreatitis

Scand J Gastroenterol Suppl

(1996)

B Beutler et al.

Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effects of endotoxin

Science

(1985)

KJ Tracey et al.

Anti cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia

Nature

(1987)

A Waage et al.

The complex pattern of cytokines in serum from patients with meningococcal septic shock: association between interleukin-6, interleukin-1, and fatal outcome

J Exp Med

(1989)

CE Hack et al.

Interleukin-8 in sepsis: relation to shock and inflammatory mediators

Infect Immun

(1992)

JC Norman

Tissue specific cytokine production during experimental acute pancreatitis: a probable mechanism for dystant organe dysfuncion

Dig Dis Sci

(1997)

C Toniatti et al.

Regulation of the human C-reactive protein gene, a major marker of inflammation and cancer

Mol Biol Med

(1990)

W Biffl et al.

Interleukin-6 in the injured patient. Marker of injury or mediator of inflammation?

Ann Surg

(1996)

N Nishimoto

Elevation of serum interleukin 6 prior to acute phase proteins on the inflammation by surgical operation

Clin Immunol Immunopathol

(1985)

DC Helfgott et al.

Rockefeller University, New York 10021 : Multiple forms of IFN-beta 2/IL-6 in serum and body fluids during acute bacterial infection

J Immunol

(1989)

T Hirano et al.

Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis

Eur J Immunol

(1988)

Cited by (47)

Organ Failure Due to Systemic Injury in Acute Pancreatitis
2019, Gastroenterology
Citation Excerpt :
Similarly, IL6 infusion in humans inhibited endotoxin induced TNF-α increase,128 and its long-term infusion led to hypoferremia and anemia,129,130 but not systemic injury. IL6131 and TNF-α132 have also been shown to have a protective role in AP, and neither these or other cytokines have been shown to induce OF.133–137 Therefore, targeting these cytokines alone may not improve outcomes in severe AP.
Acute pancreatitis may be associated with both local and systemic complications. Systemic injury manifests in the form of organ failure, which is seen in approximately 20% of all cases of acute pancreatitis and defines “severe acute pancreatitis.” Organ failure typically develops early in the course of acute pancreatitis, but also may develop later due to infected pancreatic necrosis–induced sepsis. Organ failure is the most important determinant of outcome in acute pancreatitis. We review here the current understanding of the risk factors, pathophysiology, timing, impact on outcome, and therapy of organ failure in acute pancreatitis. As we discuss the pathophysiology of severe systemic injury, the distinctions between markers and mediators of severity are highlighted based on evidence supporting their causality in organ failure. Emphasis is placed on clinically relevant end points of organ failure and the mechanisms underlying the pathophysiological perturbations, which offer insight into potential therapeutic targets to treat.
Immunopathogenesis of pancreatitis
2017, Mucosal Immunology
The conventional view of the pathogenesis of acute and chronic pancreatitis is that it is due to a genetic- or environment-based abnormality of intracellular acinar trypsinogen activation and thus to the induction of acinar cell injury that, in turn, sets in motion an intra-pancreatic inflammatory process. More recent studies, reviewed here, present strong evidence that while such trypsinogen activation is likely a necessary first step in the inflammatory cascade underlying pancreatitis, sustained pancreatic inflammation is dependent on damage-associated molecular patterns-mediated cytokine activation causing the translocation of commensal (gut) organisms into the circulation and their induction of innate immune responses in acinar cells. Quite unexpectedly, these recent studies reveal that the innate responses involve activation of responses by an innate factor, nucleotide-binding oligomerization domain 1 (NOD1), and that such NOD1 responses have a critical role in the activation/production of nuclear factor-kappa B and type I interferon. In addition, they reveal that chronic inflammation and its accompanying fibrosis are dependent on the generation of IL-33 by injured acinar cells and its downstream induction of T cells producing IL-13. These recent studies thus establish that pancreatitis is quite a unique form of inflammation and one susceptible to newer, more innovative therapy.
Immune Mechanisms of Pancreatitis
2015, Mucosal Immunology: Fourth Edition
Pancreatitis is classified into acute pancreatitis and chronic pancreatitis. Acute pancreatitis is sudden inflammation of the exocrine pancreas, whereas chronic pancreatitis is long-standing inflammation of both the exocrine and the endocrine pancreas. Pathologic intra-acinar trypsinogen activation followed by autodigestion of the pancreas has been hypothesized to be the central mechanism of pancreatitis. In addition to this view, accumulating evidence suggested the involvement of innate and adaptive immune responses in the development of pancreatitis. Microbial antigens derived from intestinal microflora and endogenous antigens from necrotic pancreatic tissue activate pathogen recognition receptors expressed in pancreatic innate immune cells to induce acute pancreatitis through the production of proinflammatory cytokines and chemokines. Enhanced immunoglobulin G4 responses and the accumulation of regulatory T cells are associated with the development of chronic pancreatitis. Thus, although autodigestion by activated pancreatic enzymes is a necessary component for pancreatic injury, pathogenic immune responses have key roles in the development of pancreatitis.
Lipolysis of visceral adipocyte triglyceride by pancreatic lipases converts mild acute pancreatitis to severe pancreatitis independent of necrosis and inflammation
2015, American Journal of Pathology
Citation Excerpt :
The improved survival with lipase inhibition suggests that the increased inflammatory response is a severity marker but not a severity mediator and is supported by the eventual reduction in serum cytokines in orlistat-treated mice electively sacrificed on the 5th day. Support for cytokines being SAP markers comes from the following: i) increases in serum IL-6 and tumor necrosis factor α secondary to UFAs,49 ii) mice administered IL-6 do not develop organ failure,65 iii) Il6 knockout mice develop SAP,65 iv) studies showing these cytokines have a protective role in AP and organ failure,66,67 and v) previous studies showing UFAs to up-regulate cytokines.35 Here we also note that the median necrosis was <10% in both the lean and ob/ob mice, similar to findings from previous reports,68 and is unaffected by lipase inhibition which prevents MSOF and mortality.
Visceral fat necrosis has been associated with severe acute pancreatitis (SAP) for over 100 years; however, its pathogenesis and role in SAP outcomes are poorly understood. Based on recent work suggesting that pancreatic fat lipolysis plays an important role in SAP, we evaluated the role of pancreatic lipases in SAP-associated visceral fat necrosis, the inflammatory response, local injury, and outcomes of acute pancreatitis (AP). For this, cerulein pancreatitis was induced in lean and obese mice, alone or with the lipase inhibitor orlistat and parameters of AP induction (serum amylase and lipase), fat necrosis, pancreatic necrosis, and multisystem organ failure, and inflammatory response were assessed. Pancreatic lipases were measured in fat necrosis and were overexpressed in 3T3-L1 cells. We noted obesity to convert mild cerulein AP to SAP with greater cytokines, unsaturated fatty acids (UFAs), and multisystem organ failure, and 100% mortality without affecting AP induction or pancreatic necrosis. Increased pancreatic lipase amounts and activity were noted in the extensive visceral fat necrosis of dying obese mice. Lipase inhibition reduced fat necrosis, UFAs, organ failure, and mortality but not the parameters of AP induction. Pancreatic lipase expression increased lipolysis in 3T3-L1 cells. We conclude that UFAs generated via lipolysis of visceral fat by pancreatic lipases convert mild AP to SAP independent of pancreatic necrosis and the inflammatory response.
Interleukin-6 is associated with obesity, central fat distribution, and disease severity in patients with acute pancreatitis
2015, Pancreatology
Acute pancreatitis (AP) is a systemic inflammatory disease, and cytokines are suggested to be related to the course of AP. Obesity and central fat distribution are considered to have been associated with severe AP. This study investigated the profile of inflammatory cytokines in AP to determine how they are related to obesity, central fat distribution, and AP severity.
Fifty-nine patients with AP were prospectively enrolled in the study. Body mass index and waist circumference were obtained at admission. Serum levels of inflammatory cytokines, IL-Iβ, IL-1ra, IL-6, TNF-α, sTNFR-I, and sTNFR-II, were measured on day 1 and 2 of AP.
Of the patients included in the study, 19 (32%) were overweight, 23 (39%) had central fat distribution, and 23 (39%) had moderate AP. IL-1ra and IL-6 were significantly higher in overweight patients compared with non-overweight patients. IL-1ra, IL-6, TNF-α, and sTNFR-I were significantly higher in patients with central fat distribution compared with patients with non-central fat distribution. IL-6, sTNFR-I, and sTNFR-II were significantly higher in patients with moderate pancreatitis compared to those with mild pancreatitis. Among the six cytokines, IL-6 was commonly elevated in patients with central fat distribution, overweight, and moderate AP. The areas under the receiver operating characteristic curves of IL-6 for predicting the association with overweight, central fat distribution, and AP severity were 0.678, 0.716, and 0.801, respectively (P < 0.05).
IL-6 is a good marker for AP severity and is associated with obesity and central fat distribution in AP patients.
Interleukin-6 in inflammatory and malignant diseases of the pancreas
2014, Seminars in Immunology
Citation Excerpt :
Therapeutic approaches targeting the IL-6-trans-signaling/gp130/STAT3/CXCL1 signaling cascade during pancreatitis showed that its inhibition attenuates the systemic complications of severe AP significantly [102]. In keeping with these findings, administering a neutralizing antibody against IL-6 after the first cerulein injection effectively suppressed the increase in serum amylase and IL-6 levels, pancreatic local damage as well as systemic lung injury in mice with cerulein and LPS induced pancreatitis [116]. These data suggest that the IL-6-trans-signaling/gp130/STAT3/CXCL1 signaling cascade is a valid target for therapy of SAP with systemic complications.
Interleukin-6 is an important pro-inflammatory cytokine strongly linked to the most burdened exocrine pancreatic diseases including acute pancreatitis, chronic pancreatitis and pancreatic cancer. However, its role in all these diseases is versatile and not completely defined. Several studies provided accumulating evidence that IL-6 is mainly involved in the JAK/STAT pathway activation promoting acute and chronic pancreatitis disease aggravation as well as pancreatic cancer initiation and progression. This review will focus on recent studies illustrating the role of IL-6 in acute and chronic pancreatitis and pancreatic oncogenesis. Further, a short overview of indicated disease pathologies will be given and the impact of IL-6 in JAK/STAT pathway, persistent STAT3 activation and cancer immunotherapy will be discussed.

View all citing articles on Scopus

^f1: Correspondence to: Salvatore Cuzzocrea, Ph. D. Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario, Via C. Valeria Gazzi 98100, Messina, Italy. Tel: (39) 090 2213644; Fax: (39) 090 2213300; E-mail: [email protected]

View full text

Regular ArticlesABSENCE OF ENDOGENOUS INTERLEUKIN-6 ENHANCES THE INFLAMMATORY RESPONSE DURING ACUTE PANCREATITIS INDUCED BY CERULEIN IN MICE

Abstract

Gastroenterology

Gastroenterology

Gastroenterology

Clin Immunol Immunopathol

Cytokine

Immunity

Immunology

Gastroenterology

J Pharmacol Meth

Anal Biochem

Gastrenterology

Gastroenterolgy

J Biol Chem

Trends Pharmacol Sci

A clinically based classification system for acute pancreatitis: summary of the international Symposium on Acute Pancreatitis, Atlanta GA, September 11 through 13, 1992

Arch Surg

Crit Care Med

Fatal panreatitis: a consequence of excessive leukocyte stimulation?

Int J Pancreatol

Monitoring of serum proteinase-antiproteinase balance and systemic inflammatory response in prognostic evaluation of acute pancreatitis: results of a prospective multicenter study

Dig Dis Sci

Inflammatory mediators in acute pancreatitis

Br J Surg

Interleukins in acute pancreatitis

Scand J Gastroenterol Suppl

Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effects of endotoxin

Science

Anti cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia

Nature

The complex pattern of cytokines in serum from patients with meningococcal septic shock: association between interleukin-6, interleukin-1, and fatal outcome

J Exp Med

Interleukin-8 in sepsis: relation to shock and inflammatory mediators

Infect Immun

Tissue specific cytokine production during experimental acute pancreatitis: a probable mechanism for dystant organe dysfuncion

Dig Dis Sci

Regulation of the human C-reactive protein gene, a major marker of inflammation and cancer

Mol Biol Med

Interleukin-6 in the injured patient. Marker of injury or mediator of inflammation?

Ann Surg

Elevation of serum interleukin 6 prior to acute phase proteins on the inflammation by surgical operation

Clin Immunol Immunopathol

Rockefeller University, New York 10021 : Multiple forms of IFN-beta 2/IL-6 in serum and body fluids during acute bacterial infection

J Immunol

Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis

Eur J Immunol

Regular Articles
ABSENCE OF ENDOGENOUS INTERLEUKIN-6 ENHANCES THE INFLAMMATORY RESPONSE DURING ACUTE PANCREATITIS INDUCED BY CERULEIN IN MICE