Pivotal Advance: Vasoactive intestinal peptide inhibits up-regulation of human monocyte TLR2 and TLR4 by LPS and differentiation of monocytes to macrophages

Abstract: Vasoactive intestinal peptide (VIP) is an immunoregulatory peptide, which inhibits LPS-in-duced cytokine secretion in myeloid cells and has beneficial effects in animal models of inflammatory diseases. We show for the first time that VIP de-creases LPS-induced up-regulation of TLR2 and TLR4 by human monocytic THP1 cells and periph-eral blood monocytes (PBM). VIP inhibited up-regulation of TLR4 expression in THP1 cells in response to LPS from Escherichia coli or the peri-odontal pathogen Porphyromonas gingivalis within 6 h poststimulation but had less of an effect on TLR2. After 24 h, P. gingivalis LPS-stimulated monocytic THP1 cells to differentiate into macro-phages, which predominantly expressed TLR2, and E. coli LPS-stimulated THP1 differentiation to predominantly TLR4-expressing macrophages. VIP decreased monocyte differentiation to macro-phages induced by LPS from either species and also reduced overall TLR2 and TLR4 expression in these cells. VIP had a similar effect on human PBM. The transcription factor PU.1 regulates TLR expression and has a central role in myeloid cell differentiation. VIP inhibited the nuclear translo-cation of PU.1 in LPS-stimulated THP-1 mono-cytes. VIP also inhibited the expression of the M-CSF receptor, which is regulated by PU.1. In sum-mary, VIP inhibited LPS-induced differentiation of monocytes with a concomitant reduction in TLR2 and TLR4 expression. Although there was differ-ential induction of TLR expression by LPS from P. gingivalis and E. coli, VIP inhibited the action of both of these LPS types on monocytes. The mech-anism of action of VIP on monocyte differentiation may be via inhibition of the transcription facto