Patients with acute pancreatitis complicated by organ failure show highly aberrant monocyte signaling profiles assessed by phospho-specific flow cytometry*

Abstract

In severe acute pancreatitis, monocytes show impaired nuclear factor kappaB and STAT1 activation, which may increase susceptibility to secondary infections. p38 activation is normal and STAT3 activation is depressed, which may contribute to maintenance of systemic inflammation. Extracellular signal-regulated kinases 1/2 activation is impaired, which may depress monocytes' transmigration and may consequently increase risk of infection. Monitoring of monocyte signaling profiles may aid in finding new therapeutic approaches and predictors of outcome of severe acute pancreatitis.

Acute pancreatitis with organ dysfunction associates with abnormal blood lymphocyte signaling: controlled laboratory study

“…Indeed, the TNF-blocking agent infliximab in co-culture with S. epidermidis , but not with E. coli or S. aureus , reduced NFκB phosphorylation, while the IL-1 receptor antagonist, anakinra, had no effect, suggesting that lymphocyte activation involved TNF among other factor(s). We have recently found that monocytes of the patients also showed reduced NFκB phosphorylation in response to bacterial stimuli [23], which agrees with our finding that TNF production by anergic monocytes is reduced [29]. Collectively, the above data shows disturbances in collaboration between patients' lymphocytes and monocytes.…”

“…Of note, the lymphocytes were double-stained with pNFκB and pp38 mAbs, and, consequently, activity of the two signaling pathways could be evaluated simultaneously. Unlike lymphocytes, the p38 phosphorylation of the patients' monocytes was normal [23]. Given that MAP-kinases are associated with the development of systemic inflammation [14], our finding raises the question of whether enhanced p38 activation provides a target for immune suppression in AP patients or if it represents a vital counter-reaction of cells to inhibit NFκB, and should therefore be strengthened rather than depressed.…”

“…The first 13 patients, whose monocyte signaling profiles are described in our previous study [23], were admitted between September 2007 and January 2009 and the last three patients between January and May 2010 (Table 1). In addition to severe AP, the inclusion criterion for the study was that the proportion of HLA-DR-positive monocytes in circulation was less than 80%.…”

“…We recently described monocyte signaling profiles in 13 AP patients with vital organ dysfunction using phospho-specific whole blood flow cytometry [23]. In the present study we describe signaling profiles of the patients' circulating lymphocytes.…”

Monocyte programmed death ligand-1 expression is an early marker for predicting infectious complications in acute pancreatitis

“…Both experimental and clinical studies suggest that patients with AP have depressed defenses against infection because of a defect in monocyte and lymphocyte signaling, which increases the risk of infection [7, 8]. In addition, a recent study showed that the shift of the Th1/Th2 balance toward Th2 responses during the course of AP leads to alterations of immune function [6, 9].…”