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

Vasoactive intestinal peptide (VIP) is an immunoregulatory peptide, which inhibits LPS‐induced cytokine secretion in myeloid cells and has beneficial effects in animal models of inflammatory diseases. We show for the first time that VIP decreases LPS‐induced up‐regulation of TLR2 and TLR4 by human monocytic THP1 cells and peripheral blood monocytes (PBM). VIP inhibited up‐regulation of TLR4 expression in THP1 cells in response to LPS from Escherichia coli or the periodontal 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 macrophages, which predominantly expressed TLR2, and E. coli LPS‐stimulated THP1 differentiation to predominantly TLR4‐expressing macrophages. VIP decreased monocyte differentiation to macrophages 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 translocation of PU.1 in LPS‐stimulated THP‐1 monocytes. VIP also inhibited the expression of the M‐CSF receptor, which is regulated by PU.1. In summary, VIP inhibited LPS‐induced differentiation of monocytes with a concomitant reduction in TLR2 and TLR4 expression. Although there was differential 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 mechanism of action of VIP on monocyte differentiation may be via inhibition of the transcription factor PU.1.

[1]  C. Martínez,et al.  VIP down-regulates TLR4 expression and TLR4-mediated chemokine production in human rheumatoid synovial fibroblasts. , 2006, Rheumatology.

[2]  J. J. Taylor,et al.  VIP Inhibits Porphyromonas gingivalis LPS-induced Immune Responses in Human Monocytes , 2005, Journal of dental research.

[3]  C. Martínez,et al.  Time‐course expression of Toll‐like receptors 2 and 4 in inflammatory bowel disease and homeostatic effect of VIP , 2005, Journal of leukocyte biology.

[4]  H. Gascan,et al.  Direct Stimulation of Human T Cells via TLR5 and TLR7/8: Flagellin and R-848 Up-Regulate Proliferation and IFN-γ Production by Memory CD4+ T Cells1 , 2005, The Journal of Immunology.

[5]  C. Martínez,et al.  cDNA Array Analysis of Cytokines, Chemokines, and Receptors Involved in the Development of TNBS‐Induced Colitis: Homeostatic Role of VIP , 2005, Inflammatory bowel diseases.

[6]  F. Liew,et al.  Negative regulation of Toll-like receptor-mediated immune responses , 2005, Nature Reviews Immunology.

[7]  C. Cutler,et al.  Oral Mucosal Endotoxin Tolerance Induction in Chronic Periodontitis , 2005, Infection and Immunity.

[8]  S. Way,et al.  Porphyromonas gingivalis Lipopolysaccharide Contains Multiple Lipid A Species That Functionally Interact with Both Toll-Like Receptors 2 and 4 , 2004, Infection and Immunity.

[9]  D. Pozo,et al.  The Significance of Vasoactive Intestinal Peptide in Immunomodulation , 2004, Pharmacological Reviews.

[10]  R. Ulevitch,et al.  Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors , 2004, Nature Immunology.

[11]  M. Grigorov,et al.  Soluble Forms of Toll-Like Receptor (TLR)2 Capable of Modulating TLR2 Signaling Are Present in Human Plasma and Breast Milk , 2003, The Journal of Immunology.

[12]  D. Maskell,et al.  Toll-Like Receptor Expression in C3H/HeN and C3H/HeJ Mice during Salmonella enterica Serovar Typhimurium Infection , 2003, Infection and Immunity.

[13]  M. Delgado,et al.  Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: players in innate and adaptive immunity. , 2003, Cellular and molecular biology.

[14]  M. Delgado,et al.  Vasoactive intestinal peptide inhibits IL-8 production in human monocytes. , 2003, Biochemical and biophysical research communications.

[15]  R. Genco,et al.  Counteracting Interactions between Lipopolysaccharide Molecules with Differential Activation of Toll-Like Receptors , 2002, Infection and Immunity.

[16]  Michael Rehli,et al.  Of mice and men: species variations of Toll-like receptor expression. , 2002, Trends in immunology.

[17]  D. Burden,et al.  Changes in vasoactive intestinal peptide in gingival crevicular fluid in response to periodontal treatment. , 2002, Journal of clinical periodontology.

[18]  M. Delgado,et al.  Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as modulators of both innate and adaptive immunity. , 2002, Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists.

[19]  T. Matsuguchi,et al.  NF-κB and STAT5 Play Important Roles in the Regulation of Mouse Toll-Like Receptor 2 Gene Expression1 , 2001, The Journal of Immunology.

[20]  M. Delgado,et al.  Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-activating Polypeptide Inhibit Nuclear Factor-κB-dependent Gene Activation at Multiple Levels in the Human Monocytic Cell Line THP-1* , 2001, The Journal of Biological Chemistry.

[21]  A. Masuda,et al.  Cutting Edge: Naturally Occurring Soluble Form of Mouse Toll-Like Receptor 4 Inhibits Lipopolysaccharide Signaling1 , 2000, The Journal of Immunology.

[22]  L. Schwarzfischer,et al.  PU.1 and Interferon Consensus Sequence-binding Protein Regulate the Myeloid Expression of the Human Toll-like Receptor 4 Gene* , 2000, The Journal of Biological Chemistry.

[23]  M. Delgado,et al.  Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-activating Polypeptide Inhibit Interleukin-12 Transcription by Regulating Nuclear Factor κB and Ets Activation* , 1999, The Journal of Biological Chemistry.

[24]  A. Baqui,et al.  Antigen activation of THP-1 human monocytic cells after stimulation with lipopolysaccharide from oral microorganisms and granulocyte-macrophage colony-stimulating factor. , 1999, Journal of periodontal research.

[25]  F. Gusovsky,et al.  Toll-like Receptor-4 Mediates Lipopolysaccharide-induced Signal Transduction* , 1999, The Journal of Biological Chemistry.

[26]  M. Rothe,et al.  Human Toll-like Receptor 2 Confers Responsiveness to Bacterial Lipopolysaccharide , 1998, The Journal of experimental medicine.

[27]  R. Lamont,et al.  Life Below the Gum Line: Pathogenic Mechanisms ofPorphyromonas gingivalis , 1998, Microbiology and Molecular Biology Reviews.

[28]  S. Orkin,et al.  The transcriptional control of hematopoiesis. , 1996, Blood.

[29]  M. Fenton,et al.  NF beta A, a factor required for maximal interleukin-1 beta gene expression is identical to the ets family member PU.1. Evidence for structural alteration following LPS activation. , 1995, Molecular immunology.

[30]  D. Tenen,et al.  The macrophage transcription factor PU.1 directs tissue-specific expression of the macrophage colony-stimulating factor receptor , 1993, Molecular and cellular biology.

[31]  R. Ulevitch,et al.  Lipopolysaccharide (LPS) partial structures inhibit responses to LPS in a human macrophage cell line without inhibiting LPS uptake by a CD14- mediated pathway , 1992, The Journal of experimental medicine.

[32]  R. Tjian,et al.  Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1. , 1987, Science.

[33]  L. Schwarzfischer,et al.  Transcriptional Regulation of the Human Toll-Like Receptor 2 Gene in Monocytes and Macrophages1 , 2002, The Journal of Immunology.

[34]  C L Carpenter,et al.  c-Jun is a JNK-independent coactivator of the PU.1 transcription factor. , 1999, The Journal of biological chemistry.

[35]  T. Ogihara,et al.  Angiotensin II type 1 receptor-mediated peroxide production in human macrophages. , 1999, Hypertension.

[36]  S. Mckercher,et al.  Myeloid development is selectively disrupted in PU.1 null mice. , 1998, Blood.