Open AccessToll‐like receptor stimulation differentially regulates vasoactive intestinal peptide type 2 receptor in macrophages
Author(s) -
Herrera Juan Luis,
GonzalezRey Elena,
FernandezMontesinos Rafael,
Quintana Francisco J.,
Najmanovich Rafael,
Pozo David
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2009.00662.x
Subject(s) - biology , vasoactive intestinal peptide , tlr2 , microbiology and biotechnology , autocrine signalling , toll like receptor , mapk/erk pathway , receptor , protein kinase a , tlr4 , signal transduction , kinase , biochemistry , innate immune system , neuropeptide
Vasoactive intestinal peptide (VIP) was originally isolated as a vasodilator intestinal peptide, then as a neuropeptide. In the immune system, VIP is described as an endogenous macrophage‐deactivating factor. VIP exerts its immunological actions in a paracrine and/or autocrine manner, through specific receptors. However, very little is known about the molecular regulation of VIP type 2 receptor (VPAC 2 ) in the immune system. We now report that different toll‐like receptor (TLR) ligands selectively regulate the VPAC 2 receptor gene and show a gene repression system controlled by key protein kinase signalling cascades in macrophages. VPAC 2 gene expression is regulated by gram‐positive (TLR2 ligands) and gram‐negative bacteria wall constituents (TLR4 ligands). Moreover, VPAC 2 is tightly regulated: TLR2‐ or TLR2/6‐ but not TLR2/1‐mediated mechanisms are responsible for the induction of VPAC 2 . TLR stimulation by viral or bacterial nucleic acids did not modify the VPAC 2 mRNA levels. Remarkably, imiquimod – a synthetic TLR7 ligand – led to a potent up‐regulation of VPAC 2 gene expression. TLR5 stimulation by flagellin present in gram‐positive and gram‐negative bacteria did not affect VPAC 2 mRNA. The p38 mitogen‐activated protein kinase (MAPK) activity accounted for the TLR4‐mediated induction of VPAC 2 gene expression. Surprisingly, our data strongly suggest for the first time a tightly repressed control of VPAC 2 mRNA induction by elements downstream of MAPK kinase 1/2, PI3K/Akt, and particularly Jun‐NH 2 ‐terminal kinase signalling pathways.