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

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

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

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

Original languageEnglish (US)
Pages (from-to)6263-6272
Number of pages10
JournalJournal of Immunology
Volume179
Issue number9
StatePublished - Nov 1 2007
Externally publishedYes

Fingerprint

Adrenomedullin
Peroxisome Proliferator-Activated Receptors
Carrier Proteins
Anti-Inflammatory Agents
Hormones
Sepsis
MAP Kinase Signaling System
Cyclic AMP
TYK2 Kinase
Bucladesine
Endotoxemia
Multiple Organ Failure
Genistein
Septic Shock
Small Interfering RNA
Shock
Therapeutics
Macrophages
Cytokines

ASJC Scopus subject areas

  • Immunology

Cite this

Vasoactive hormone adrenomedullin and its binding protein : Anti-inflammatory effects by up-regulating peroxisome proliferator-activated receptor-γ. / Miksa, Michael; Wu, Rongqian; Cui, Xiaoxuan; Dong, Weifeng; Das, Padmalaya; Simms, H. Hank; Ravikumar, Thanjavur S.; Wang, Ping.

In: Journal of Immunology, Vol. 179, No. 9, 01.11.2007, p. 6263-6272.

Research output: Contribution to journalArticle

Miksa, M, Wu, R, Cui, X, Dong, W, Das, P, Simms, HH, Ravikumar, TS & Wang, P 2007, 'Vasoactive hormone adrenomedullin and its binding protein: Anti-inflammatory effects by up-regulating peroxisome proliferator-activated receptor-γ', Journal of Immunology, vol. 179, no. 9, pp. 6263-6272.
Miksa, Michael ; Wu, Rongqian ; Cui, Xiaoxuan ; Dong, Weifeng ; Das, Padmalaya ; Simms, H. Hank ; Ravikumar, Thanjavur S. ; Wang, Ping. / Vasoactive hormone adrenomedullin and its binding protein : Anti-inflammatory effects by up-regulating peroxisome proliferator-activated receptor-γ. In: Journal of Immunology. 2007 ; Vol. 179, No. 9. pp. 6263-6272.
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