Role of Redox Signaling, Protein Phosphatases and Histone Acetylation in the Inflammatory Cascade in Acute Pancreatitis: Therapeutic Implications

Author(s): Javier Escobar, Javier Pereda, Alessandro Arduini, Juan Sandoval, Luis Sabater, Luis Aparisi, Maximo Vento, Gerardo Lopez-Rodas, Juan Sastre.

Journal Name: Inflammation & Allergy - Drug Targets (Discontinued)
(Formerly Current Drug Targets - Inflammation & Allergy)

Volume 9 , Issue 2 , 2010

Abstract:

Acute pancreatitis starts as a local inflammation of the pancreatic tissue but often leads to the systemic inflammatory response syndrome and death by multiple organ failure. Pro-inflammatory cytokines, particularly TNF-α and Il-1β, play a pivotal role together with oxidative stress and glutathione depletion in the inflammatory response in this disease. Most inflammatory mediators act through mitogen activated protein kinases and nuclear factor κB. Nevertheless, elucidation of the precise mechanisms involved in activation and attenuation phases of the inflammatory cascade is still underway. Redox signaling mediated by inactivation of protein phosphatases and histone acetylation triggered by histone acetyltransferases, particularly CBP/p300, decisively contribute to the activation phase of the inflammatory cascade. Reversible oxidation of thiols in serine threonine protein phosphatase PP2A and in protein tyrosin phosphatases SHP1, SHP2 and CD45 leads to their inactivation generally by formation of intramolecular disulfides. Consequently, oxidative stress promotes the activation of MAP kinases through the inactivation of protein phosphatases, which act as sensors of the cellular redox state. On the other hand, histone deacetylases together with serine threonine protein phosphatases PP1 and PP2A and dual specificity phosphatases down-regulate the expression of pro-inflammatory genes in the attenuation phase. Treatment with phosphodiesterase inhibitors, such as pentoxifylline, in the very early stage of the disease prevents the loss of pancreatic PP2A activity abrogating the recruitment of histone acetyltransfereases to the promoters of proinflammatory genes and their up-regulation. Inhibitors of histone deacetylases are also proposed as potential therapy in acute pancreatitis, and their therapeutic window discussed.

Keywords: Acute pancreatitis, cytokines, serine/threonine protein phosphatases, PP2A, cAMP, CBP, phosphodiesterase inhibitors, pentoxifylline

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Article Details

VOLUME: 9
ISSUE: 2
Year: 2010
Page: [97 - 108]
Pages: 12
DOI: 10.2174/187152810791292773
Price: $58

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