Decreased expression of Toll-like receptor 2 and 4 on macrophages in experimental severe acute pancreatitis.
In severe acute pancreatitis (SAP), immunologic impairment in the early phase may be linked to subsequent infectious complications that are main contributor to the high mortality. Toll-like receptors (TLRs) recognize microorganisms as the innate immune system, and are involved in host defense mechanism. TLR2 recognizes lipoteichoic acid (LTA) of gram-positive bacteria, and TLR4 recognizes lipopolysaccharide (LPS) of gram-negative bacilli. This study aimed to investigate the expression of TLRs on macrophages and their TLRs-mediated cytokine production in rat SAP. SAP was induced by retrograde injection of 3% sodium deoxycholate into the biliopancreatic duct in male Wistar rats. Macrophages were isolated from bronchoalveolar lavage fluid 6 hours after induction of SAP. The expression of TLR2 and TLR4 was analyzed by real-time RT-PCR and western blotting. TNF-alpha release from macrophages was estimated after 4-hour stimulation of LTA or LPS. Endotoxin/bacterial translocation (E/BT) was also evaluated in this model. The expression of TLR2 (mRNA and protein) and LTA-mediated TNF-alpha production were significantly decreased in SAP compared with control. The expression of TLR4 (mRNA and protein) and LPS-mediated TNF-alpha production was also significantly decreased in SAP compared with control. E/BT occurred 18 hours after induction of SAP. These results suggest that the impaired responsiveness to LTA and LPS of macrophages is derived from decreased expression of TLR2 and TLR4, respectively. This suppression of immune response in the early phase may be implicated in the mechanism of infectious complications.
Matsumura
Naoki
N
Division of Gastroenterological Surgery, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Takeyama
Yoshifumi
Y
Ueda
Takashi
T
Yasuda
Takeo
T
Shinzeki
Makoto
M
Sawa
Hidehiro
H
Nakajima
Takahiro
T
Kuroda
Yoshikazu
Y
D000208:Acute Disease; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D008070:Lipopolysaccharides / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010195:Pancreatitis / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D013682:Teichoic Acids / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics*
D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013682:Teichoic Acids; C495343:Tlr2 protein, rat; C495347:Tlr4 protein, rat; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C009900:lipoteichoic acid