Induction of monocyte chemoattractant protein-1 expression by angiotensin II in the pancreatic islets and beta-cells.
Angiotensin II (AngII), the principal hormone of the renin-angiotensin system, is actively generated in the pancreas and has been suggested as a key mediator of inflammation. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that plays an important role in the recruitment of mononuclear cells into the pancreatic islets. In this study, we investigated the potential molecular basis for the role of AngII in islet inflammation through studying its effect on MCP-1. AngII significantly increased the expression of MCP-1 mRNA and protein in the RINm5F beta-cell line and activated MCP-1 promoter. AngII-MCP-1 mRNA induction was inhibited by an AngII type 1 receptor antagonist but was unchanged by an AngII type 2 receptor antagonist. AngII-MCP-1 induction was inhibited by the tyrosine kinase inhibitor genistein, suggesting a MAPK signaling mechanism. AngII activated the phosphorylation of ERK1/2 but not p38 or c-Jun NH(2)-terminal MAPKs. Inhibition of ERK1/2 activation reduced the AngII-induced MCP-1 synthesis. In nonobese diabetic mice pancreata, the temporal pattern of angiotensin-converting enzyme expression correlated well with progression of insulitis and beta-cell destruction. Immunostaining of pancreatic serial sections show colocalization of angiotensin-converting enzyme with MCP-1 in beta-cells in the islets. In freshly isolated islets from normoglycemic mice, AngII alone and in combination with IL-1beta elicited an inflammatory response by stimulation of MCP-1. Our data suggest a positive autocrine/paracrine action for the local pancreatic AngII-generating system during insulitis and provide the first insight into an AngII-initiated signal transduction pathway that regulates MCP-1 as a possible inflammatory mechanism in the islets.
Chipitsyna
Galina
G
Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Gong
Qiaoke
Q
Gray
Chance F
CF
Haroon
Yasir
Y
Kamer
Erdinc
E
Arafat
Hwyda A
HA
D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000503:physiopathology*; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006943:Hyperglycemia / Q000276:immunology / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D007340:Insulinoma; D053583:Interleukin-1beta / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010190:Pancreatic Neoplasms; D011401:Promoter Regions, Genetic / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D007093:Imidazoles; D053583:Interleukin-1beta; D011725:Pyridines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C073402:PD 123319; D011505:Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019808:Losartan