Crohn's disease (CD) is a chronic intestinal inflammatory pathology, which develops as a result of innate immune signals, such as the activation of
Toll-like receptors (TLRs), and adaptive immune signals, including Th1
cytokine release. We have recently demonstrated in TNBS-induced
colitis, a murine model of CD, that VIP plays a homeostatic role, by reducing TNBS-induced TLR2 and TLR4 expression to control levels. The purpose of this paper is to elucidate for the first time, the physiological relevance of VIP specific control of innate and adaptive immune responses through TLR2 and TLR4
ligands. In addition, we investigated the effect of VIP on regulatory activity of T regulatory (Treg) cells in the TNBS-
colitis model. First, we found that VIP downregulated the inflammatory response elicited in mesenteric lymph node cell cultures by treatment with the TLR2
ligand Pam3Cys, or the TLR4
ligand lipopolysaccharide (LPS), reducing the production of the
chemokine CXCL1. Also, treatment with VIP impaired the induction of Th1 responses by decreasing p70
interleukin (IL)-12 and
interferon gamma (IFN-gamma) levels after TLR2/TLR4 stimulation in culture. Besides, VIP treatment restored in vivo the numbers of TLR2 and TLR4 positive CD4+CD25+ T lymphocytes, augmented by TNBS administration, and increased the expression of molecules involved in regulatory T cell function, such as Foxp3 and
TGF-beta. In conclusion, the ability of VIP to down-regulate uncontrolled
inflammation by targeting TLR-mediated responses and regulatory T cell activity could be used as a new alternative
therapy for intestinal inflammatory/autoimmune disorders.