Vasoactive hormone adrenomedullin and its binding protein: anti-inflammatory effects by up-regulating peroxisome proliferator-activated receptor-gamma

• Published in: The Journal of immunology (1950) Vol. 179; no. 9; pp. 6263 - 6272
• Main Authors: Miksa, Michael, Wu, Rongqian, Cui, Xiaoxuan, Dong, Weifeng, Das, Padmalaya, Simms, H Hank, Ravikumar, Thanjavur S, Wang, Ping
• Format: Journal Article
• Language: English
• Published: United States 01.11.2007
• Subjects: Adrenomedullin - pharmacology; Animals; Cell Line; Complement Factor H - pharmacology; Cyclic AMP - metabolism; Endotoxemia - chemically induced; Endotoxemia - genetics; Endotoxemia - metabolism; Focal Adhesion Kinase 2 - metabolism; Inflammation - genetics; Inflammation - metabolism; Lipopolysaccharides - pharmacology; Male; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; PPAR gamma - genetics; PPAR gamma - metabolism; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha - metabolism; Up-Regulation - drug effects
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.179.9.6263

Sepsis is a critical inflammatory condition from which numerous patients die due to multiple organ failure and septic shock. The vasoactive hormone adrenomedullin (AM) and its binding protein (AMBP-1) are beneficial in sepsis by abrogating the progression to irreversible shock and decreasing proinflammatory cytokine release. To investigate the anti-inflammatory mechanism, we studied to determine the effect of the AM/AMBP-1 complex on peroxisome proliferator-activated receptor-gamma (PPAR-gamma) expression and activation by using RAW264.7 cells and a rat endotoxemia model. LPS treatment significantly decreased PPAR-gamma expression in vivo and in vitro and was associated with increased TNF-alpha production. Treatment with AM/AMBP-1 for 4 h completely restored PPAR-gamma levels in both models, resulting in TNF-alpha suppression. In a knockdown model using small interfering RNA in RAW264.7 macrophages, AM/AMBP-1 failed to suppress TNF-alpha production in the absence of PPAR-gamma. LPS caused the suppression of intracellular cyclic AMP (cAMP), which was prevented by simultaneous AM/AMBP-1 treatment. Although incubation with dibutyryl cAMP significantly decreased LPS-induced TauNuF-alpha release, it did not alter PPAR-gamma expression. Through inhibition studies using genistein and PD98059 we found that the Pyk-2 tyrosine kinase-ERK1/2 pathway is in part responsible for the AM/AMBP-1-mediated induction of PPAR-gamma and the anti-inflammatory effect. We conclude that AM/AMBP-1 is protective in sepsis due to its vasoactive properties and direct anti-inflammatory effects mediated through both the cAMP-dependent pathway and Pyk-2-ERK1/2-dependent induction of PPAR-gamma.