Submitted on February 1, 2007
Accepted on October 17, 2007
Altered anti-inflammatory response of mononuclear cells to neuropeptide PACAP is associated with deregulation of NF-kappaB in chronic pancreatitis
Christoph W Michalski1*, Federico Selvaggi2, Michael Bartel3, Tomas Mitkus4, Andrej Gorbachevski4, Thomas Giese5, Pierluigi Di Sebastiano4, Nathalia A Giese4, and Helmut Friess1
1 General Surgery, Technische Universitat Munchen, Munich, Germany
2 General Surgery, University of Heidelberg, Germany
3 General Surgery, University of Heidelberg, United States
4 General Surgery, University of Heidelberg, Heidelberg, Germany
5 Institute of Immunology, University of Heidelberg, Germany
* To whom correspondence should be addressed. E-mail: christoph.michalski{at}gmx.de.
Although recognized that neurogenic influences contribute to progression of chronic inflammatory diseases, the molecular basis of neuroimmune interactions in the pathogenesis of chronic pancreatitis (CP) is not well defined. Here, we report that responsiveness of peripheral blood mononuclear cells (PBMC) to the neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) is altered in CP. Expression of PACAP and its receptors in human CP was analyzed using quantitative RT-PCR, laser-capture microdissection and immunohistochemistry. Regulation of PACAP expression was studied in co-culture systems using macrophages and acinar cells. Responsiveness of donor and CP-PBMC to PACAP was determined based on cytokine profiles and NF-kappaB activation of LPS- or LPS+PACAP-exposed cells. Although donor and CP-PBMC responded equally to LPS, PACAP-mediated counteraction of LPS-induced cytokine response was switched from inhibiting TNFalpha to decreasing IL 1beta and increasing IL-10 secretion. The change of PACAP-mediated anti inflammatory pattern was associated with altered activation of NF-kappaB: compared to LPS alone, a combination of LPS and PACAP had no effect on NFkappaB-p65 nuclear translocation in CP-PBMC, whereas NFkappaB was significantly decreased in donor PBMC. According to laser-capture microdissection and co-culture experiments, PBMC also contributed to generation of a PACAP-rich intrapancreatic environment by up regulating PACAP expression in macrophages encountering apoptotic pancreatic acini. The nociceptive status of CP patients correlated with pancreatic PACAP levels and with IL-10 bias of PACAP-exposed CP-PBMC. Thus, the ability of PBMC to produce and to respond to PACAP might influence neuroimmune interactions that regulate pain and inflammation in CP.
