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Vasoactive Hormone Adrenomedullin and Its Binding Protein: Anti-Inflammatory Effects by Up-Regulating Peroxisome Proliferator-Activated Receptor-¹

Michael Miksa^*,, Rongqian Wu^*,, Xiaoxuan Cui^*,, Weifeng Dong^*,, Padmalaya Das^*,, H. Hank Simms, Thanjavur S. Ravikumar^*, and Ping Wang^2,*,

^* Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, and Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, NY 11030; and Department of Surgery, Albert Einstein Medical Center, Philadelphia, PA 19141

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- (PPAR-) expression and activation by using RAW264.7 cells and a rat endotoxemia model. LPS treatment significantly decreased PPAR- expression in vivo and in vitro and was associated with increased TNF- production. Treatment with AM/AMBP-1 for 4 h completely restored PPAR- levels in both models, resulting in TNF- suppression. In a knockdown model using small interfering RNA in RAW264.7 macrophages, AM/AMBP-1 failed to suppress TNF- production in the absence of PPAR-. 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 TNF- release, it did not alter PPAR- 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- 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-.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 HL076179 and R01 GM057468 (to P.W.).

² Address correspondence and reprint requests to Dr. Ping Wang, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030. E-mail address: PWang{at}nshs.edu

³ Abbreviations used in this paper: AM, adrenomedullin; AMBP-1, adrenomedullin binding protein; BW, body weight; cAMP, cyclic AMP; CLP, cell ligation and puncture; CRLR, calcitonin receptor-like receptor; DBcAMP, dibutyryl cAMP; 15dPGJ₂, 15-deoxy ^12,14 prostaglandin J₂; IBMX, 1-methyl-3-isobutylxanthine; PDE, phosphodiesterase; PPAR-, peroxisome proliferator-activated receptor-; Pyk-2, proline-rich tyrosine kinase-2; RAMP, receptor activity-modifying protein; siRNA, small interfering RNA; RCP, receptor component protein; ROL, rolipram.