Chemokine receptor CCR5 deficiency exacerbates cerulein-induced acute pancreatitis in mice.
Acute pancreatitis (AP) is an inflammatory disease involving the production of different cytokines and chemokines and is characterized by leukocyte infiltration. Because the chemokine receptor CCR5 and its ligands [the CC chemokines CCL3/MIP-1alpha, CCL4/MIP-1beta, and CCL5/regulated upon activation, normal T cell expressed and secreted (RANTES)] regulate leukocyte chemotaxis and activation, we investigated the expression of CCR5 ligands and the role of CCR5 and its ligands in experimental AP in mice. AP was induced by hourly intraperitoneal injections of cerulein in CCR5-deficient (CCR5(-/-)) or wild-type (WT) mice. Induction of AP by cerulein resulted in an early increase of pancreatic CCL2, CCL3, and CCL4 mRNA expression, whereas CCL5 mRNA expression occurred later. CCR5(-/-) mice developed a more severe pancreatic injury than WT mice during cerulein-induced AP, as assessed by a more pronounced increase in serum amylase and lipase levels and by more severe pancreatic edema, inflammatory infiltrates (mainly neutrophils), and necrosis. CCR5(-/-) mice also exhibited increased production of CCL2/MCP-1, CCL3/MIP-1alpha, and CCL4/MIP-1beta during the course of cerulein-induced AP. In vivo simultaneous neutralization of CC chemokines with monoclonal antibodies in CCR5(-/-) mice reduced the severity of cerulein-induced AP, indicating a role of CC chemokines in exacerbating the course of AP in the absence of CCR5. Moreover, simultaneous neutralization of CCR5 ligands in WT mice also reduced the severity of cerulein-induced AP. In conclusion, lack of the chemokine receptor CCR5 exacerbates experimental cerulein-induced AP and leads to increased levels of CC chemokines and a more pronounced pancreatic inflammatory infiltrate, suggesting that CCR5 expression can modulate severity of AP.
Moreno
Christophe
C
Division of Gastroenterology and Hepatopancreatology, Erasme Hospital, Brussels B 1070, Belgium. cmoreno@ulb.ac.be
Nicaise
Charles
C
Gustot
Thierry
T
Quertinmont
Eric
E
Nagy
Nathalie
N
Parmentier
Marc
M
Louis
Hubert
H
Devière
Jacques
J
D000208:Acute Disease; D000818:Animals; D002108:Ceruletide; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D019713:Receptors, CCR5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D019713:Receptors, CCR5; D002108:Ceruletide