Invariant natural killer T (iNKT) cells are key innate immune cells implicated in the pathogenesis of many diseases. Glucagon-like peptide-1 (GLP-1) is an incretin hormone implicated in regulating blood glucose and body weight. We recently demonstrated that GLP-1 is a regulator of iNKT cell function and that inflammatory conditions such as psoriasis, rheumatoid arthritis and ulcerative colitis improve following GLP-1 therapy. GLP-1 is one of several post-prandial gut hormones, including peptide YY (PYY), cholecystokinin (CCK) and ghrelin, each with a distinct metabolic function.
We investigated iNKT cell lines for expression of PYY, CCK and ghrelin receptors by PCR and examined receptor activation impact on cell function by ELISA and flow cytometry.
A PYY receptor (PYY-R) was identified and, as was previously demonstrated with GLP-1, PYY-R activation induced the anti-inflammatory transcription factor CREB and inhibited the pro-inflammatory transcription factor NFκB. This translated into reduced production of the pro-inflammatory cytokine IFN-γ (600450 pg/ml, P<0.01) but not the anti-inflammatory cytokine IL4 (350349 pg/ml). We also demonstrated increased tumour cell lysis by PYY-treated iNKT cells (6 vs 12% of tumour cells lysed (P<0.001).
Stimulation of the CCK receptor resulted in activation of the transcription factor NFκB but had no effect on CREB. This resulted in an increase in cytokine production of both IFN-γ and IL13 (300400 and 280370 pg/ml, respectively). We identified a ghrelin receptor on the iNKT cell, but activation had no impact on cell function or the CREB and NFκB transcription factors.
We conclude that post-prandial gut hormones differentially impact and regulate innate immune cell function and may have therapeutic potential as immunomodulatory agents in autoimmunity and malignancy.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.
05 - 09 May 2012
European Society of Endocrinology