Does nicotine influence cytokine profile and subsequent cell cycling/apoptotic responses in inflammatory bowel disease?

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http://www3.interscience.wiley.com/journal/120751090/abstract?CRETRY=1 & SRETRY=0

Original Article

Does nicotine influence cytokine profile and subsequent cell cycling/apoptotic responses in inflammatory bowel disease?

n C. Aldhous, PhD 1 *, Robin J. Prescott, PhD 2, Simon , MB BS 1, Kay , BSc (Hons) 3, Waterfall, PhD 3, Jack Satsangi, DPhil 1

1Gastrointestinal Unit, School of Clinical and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, UK2Medical Statistics Unit, School of Clinical Sciences and Community Health, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, UK3 Laboratory, Division of Oncology, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, UK

email: n C. Aldhous (maldhous@...)

*Correspondence to n C. Aldhous, Gastrointestinal Unit, 2nd Floor, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh. EH4 2XU Scotland, UK

Funded by: National Association for Crohn's and Colitis Chief Scientist's Office of the ish Executive

Keywords

cytokines • cell cycle • inflammatory bowel disease

Abstract

Background: Smoking differentially influences susceptibility to the inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis (UC). We investigated the effects of nicotine on cytokine, cell cycle, and apoptotic responses in peripheral blood mononuclear cells (PBMCs) from IBD patients and healthy controls (HCs).

Methods: PBMCs from IBD patients and HC were stimulated with lipopolysaccharide (LPS; 1 g/mL) or phytohemagglutinin (PHA, 5 or 0.5 g/mL), ± nicotine (1, 10, 100 g/mL). Cytokines (IL1, IL2, IL10, IL12/IL23p40, TGF, TNF) were measured in supernatants at 24 hours. After 72 hours cells were analyzed by flow cytometry for cell cycle and apoptosis. Statistical modeling was used to identify interactions between cytokines and cell cycle / apoptosis and minimize confounding effects.

Results: Stimulation by LPS and PHA (5 g/mL) increased IL12/IL23p40 production from CD and UC versus HC (P < 0.05); PHA (0.5 g/mL) increased IL1 in UC and decreased TGF from CD and UC (P < 0.01). In all groups, nicotine reduced LPS- and PHA (0.5 g/mL)-stimulated production of IL1, IL10, TGF, and TNF (P < 0.001). Cell cycle analysis showed that PHA, but not LPS, induced proliferation and decreased G0/G1 resting cells in CD and UC versus HC (P < 0.001). Nicotine decreased PHA-stimulated S-phase proliferation and increased G0/G1 resting cells (P < 0.01). Modeling showed independent associations between IL12/IL23p40 and apoptosis (P = 0.01), IL1 and resting cells (P = 0.006), TNF and proliferating cells (P < 0.001). Disease activity and smoking habit had no effect.

Conclusions: Dysregulated cytokine profiles in UC and CD are associated with specific alterations in cell cycle responses; these effects may be modified by nicotine, and potentially by anticytokine therapies.

(Inflamm Bowel Dis 2008)

Received: 14 December 2007; Accepted: 2 May 2008

Digital Object Identifier (DOI)10.1002/ibd.20523