Time course of signaling profiles of blood leukocytes in acute pancreatitis and sepsis

Abstract

Activation of intracellular signaling pathways in circulating leukocytes represents an early step in systemic immune-inflammatory response occurring e.g. in acute pancreatitis (AP) and sepsis. Previously, we found aberrations in the phosphorylation of leukocyte signaling proteins in patients with sepsis or AP (measured <48 h from hospital admission) resembling each other and associating with AP severity. Of these patients, those with sepsis or severe AP complicated by persistent organ dysfunction (OD+, n = 17) and patients with moderately severe AP (OD-, n = 6) were followed up in this study by measuring the phosphorylations at two additional time points (2–4 and 5–8 days after the initial sample) using phosphospecific whole blood flow cytometry. Twenty-eighty healthy subjects served as controls (HC). Constitutive STAT3 phosphorylation (pSTAT3) declined in monocytes and neutrophils of OD-/OD + and in lymphocytes of OD + and remained higher in OD- than HC. Monocytes of OD-/OD + showed low pSTAT3 and pSTAT1 levels in response to IL-6 through follow-up. Monocyte pNF-κB levels in response to TNF, LPS and E. coli in OD+, to E. coli in OD-, and lymphocyte pNF-κB levels in response to TNF in OD- increased during follow-up but remained lower than in HC, and neutrophil pNF-κB levels in response to TNF declined in OD-. Phorbol myristate acetate + Ca²⁺ ionophore-stimulated pERK1/2 decreased in neutrophils of OD−/OD+. To conclude, in patients with moderately severe or severe AP or sepsis, improvement and molecular events contributing to OD can be assessed at the level of blood leukocyte signaling.

Keywords:

• Pancreatitis
• sepsis
• leukocytes
• flow cytometry
• signal transduction

Acknowledgments

Ms Terhi Salonen is warmly acknowledged for excellent technical assistance.

Disclosure statement

The authors declare that they have no conflict of interest.

Additional information

Funding

The study was supported, in part, by Helsinki University Hospital Research Funds, Helsinki, Finland.