A novel MyD-1 (SIRP-1{alpha}) signaling pathway that inhibits LPS-induced TNF{alpha} production by monocytes

R.E. Smith, V. Patel, S.D. Seatter, M.R. Deehan, M.H. Brown, G.P. Brooke, H.S. Goodridge, C.J. Howard, K.P. Rigley, W. Harnett, M.M. Harnett

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

MyD-1 (CD172) is a member of the family of signal regulatory phosphatase (SIRP) binding proteins, which is expressed on human CD14+ monocytes and dendritic cells. We now show a novel role for MyD-1 in the regulation of the innate immune system by pathogen products such as lipopolysaccharide (LPS), purified protein derivative (PPD), and Zymosan. Specifically, we demonstrate that ligation of MyD-1 on peripheral blood mononuclear cells (PBMCs) inhibits tumor necrosis factor alpha (TNF{alpha}) secretion but has no effect on other cytokines induced in response to each of these products. In an attempt to understand the molecular mechanisms underlying this surprisingly selective effect we investigated signal transduction pathways coupled to MyD-1. Ligation of the SIRP was found to recruit the tyrosine phosphatase SHP-2 and promote sequential activation of phosphatidylinositol (PI) 3-kinase, phospholipase D, and sphingosine kinase. Inhibition of LPS-induced TNF{alpha} secretion by MyD-1 appears to be mediated by this pathway, as the PI 3-kinase inhibitor wortmannin restores normal LPS-driven TNF{alpha} secretion. MyD-1-coupling to this PI 3-kinase-dependent signaling pathway may therefore present a novel target for the development of therapeutic strategies for combating TNF{alpha} production and consequent inflammatory disease.
LanguageEnglish
Pages2532-2540
Number of pages8
JournalBlood
Volume102
DOIs
Publication statusPublished - 2003

Fingerprint

Phosphatidylinositol 3-Kinase
Phosphoric Monoester Hydrolases
Lipopolysaccharides
Monocytes
Tumor Necrosis Factor-alpha
Ligation
Phospholipase D
Signal transduction
Zymosan
Immune system
Pathogens
Dendritic Cells
Tyrosine
Immune System
Signal Transduction
Blood Cells
Carrier Proteins
Blood
Chemical activation
Cytokines

Keywords

  • signaling pathway
  • LPS-induced TNF{alpha} production
  • LPS
  • monocytes

Cite this

Smith, R. E., Patel, V., Seatter, S. D., Deehan, M. R., Brown, M. H., Brooke, G. P., ... Harnett, M. M. (2003). A novel MyD-1 (SIRP-1{alpha}) signaling pathway that inhibits LPS-induced TNF{alpha} production by monocytes. Blood, 102, 2532-2540. https://doi.org/10.1182/blood-2002-11-3596
Smith, R.E. ; Patel, V. ; Seatter, S.D. ; Deehan, M.R. ; Brown, M.H. ; Brooke, G.P. ; Goodridge, H.S. ; Howard, C.J. ; Rigley, K.P. ; Harnett, W. ; Harnett, M.M. / A novel MyD-1 (SIRP-1{alpha}) signaling pathway that inhibits LPS-induced TNF{alpha} production by monocytes. In: Blood. 2003 ; Vol. 102. pp. 2532-2540.
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abstract = "MyD-1 (CD172) is a member of the family of signal regulatory phosphatase (SIRP) binding proteins, which is expressed on human CD14+ monocytes and dendritic cells. We now show a novel role for MyD-1 in the regulation of the innate immune system by pathogen products such as lipopolysaccharide (LPS), purified protein derivative (PPD), and Zymosan. Specifically, we demonstrate that ligation of MyD-1 on peripheral blood mononuclear cells (PBMCs) inhibits tumor necrosis factor alpha (TNF{alpha}) secretion but has no effect on other cytokines induced in response to each of these products. In an attempt to understand the molecular mechanisms underlying this surprisingly selective effect we investigated signal transduction pathways coupled to MyD-1. Ligation of the SIRP was found to recruit the tyrosine phosphatase SHP-2 and promote sequential activation of phosphatidylinositol (PI) 3-kinase, phospholipase D, and sphingosine kinase. Inhibition of LPS-induced TNF{alpha} secretion by MyD-1 appears to be mediated by this pathway, as the PI 3-kinase inhibitor wortmannin restores normal LPS-driven TNF{alpha} secretion. MyD-1-coupling to this PI 3-kinase-dependent signaling pathway may therefore present a novel target for the development of therapeutic strategies for combating TNF{alpha} production and consequent inflammatory disease.",
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Smith, RE, Patel, V, Seatter, SD, Deehan, MR, Brown, MH, Brooke, GP, Goodridge, HS, Howard, CJ, Rigley, KP, Harnett, W & Harnett, MM 2003, 'A novel MyD-1 (SIRP-1{alpha}) signaling pathway that inhibits LPS-induced TNF{alpha} production by monocytes' Blood, vol. 102, pp. 2532-2540. https://doi.org/10.1182/blood-2002-11-3596

A novel MyD-1 (SIRP-1{alpha}) signaling pathway that inhibits LPS-induced TNF{alpha} production by monocytes. / Smith, R.E.; Patel, V.; Seatter, S.D.; Deehan, M.R.; Brown, M.H.; Brooke, G.P.; Goodridge, H.S.; Howard, C.J.; Rigley, K.P.; Harnett, W.; Harnett, M.M.

In: Blood, Vol. 102, 2003, p. 2532-2540.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A novel MyD-1 (SIRP-1{alpha}) signaling pathway that inhibits LPS-induced TNF{alpha} production by monocytes

AU - Smith, R.E.

AU - Patel, V.

AU - Seatter, S.D.

AU - Deehan, M.R.

AU - Brown, M.H.

AU - Brooke, G.P.

AU - Goodridge, H.S.

AU - Howard, C.J.

AU - Rigley, K.P.

AU - Harnett, W.

AU - Harnett, M.M.

PY - 2003

Y1 - 2003

N2 - MyD-1 (CD172) is a member of the family of signal regulatory phosphatase (SIRP) binding proteins, which is expressed on human CD14+ monocytes and dendritic cells. We now show a novel role for MyD-1 in the regulation of the innate immune system by pathogen products such as lipopolysaccharide (LPS), purified protein derivative (PPD), and Zymosan. Specifically, we demonstrate that ligation of MyD-1 on peripheral blood mononuclear cells (PBMCs) inhibits tumor necrosis factor alpha (TNF{alpha}) secretion but has no effect on other cytokines induced in response to each of these products. In an attempt to understand the molecular mechanisms underlying this surprisingly selective effect we investigated signal transduction pathways coupled to MyD-1. Ligation of the SIRP was found to recruit the tyrosine phosphatase SHP-2 and promote sequential activation of phosphatidylinositol (PI) 3-kinase, phospholipase D, and sphingosine kinase. Inhibition of LPS-induced TNF{alpha} secretion by MyD-1 appears to be mediated by this pathway, as the PI 3-kinase inhibitor wortmannin restores normal LPS-driven TNF{alpha} secretion. MyD-1-coupling to this PI 3-kinase-dependent signaling pathway may therefore present a novel target for the development of therapeutic strategies for combating TNF{alpha} production and consequent inflammatory disease.

AB - MyD-1 (CD172) is a member of the family of signal regulatory phosphatase (SIRP) binding proteins, which is expressed on human CD14+ monocytes and dendritic cells. We now show a novel role for MyD-1 in the regulation of the innate immune system by pathogen products such as lipopolysaccharide (LPS), purified protein derivative (PPD), and Zymosan. Specifically, we demonstrate that ligation of MyD-1 on peripheral blood mononuclear cells (PBMCs) inhibits tumor necrosis factor alpha (TNF{alpha}) secretion but has no effect on other cytokines induced in response to each of these products. In an attempt to understand the molecular mechanisms underlying this surprisingly selective effect we investigated signal transduction pathways coupled to MyD-1. Ligation of the SIRP was found to recruit the tyrosine phosphatase SHP-2 and promote sequential activation of phosphatidylinositol (PI) 3-kinase, phospholipase D, and sphingosine kinase. Inhibition of LPS-induced TNF{alpha} secretion by MyD-1 appears to be mediated by this pathway, as the PI 3-kinase inhibitor wortmannin restores normal LPS-driven TNF{alpha} secretion. MyD-1-coupling to this PI 3-kinase-dependent signaling pathway may therefore present a novel target for the development of therapeutic strategies for combating TNF{alpha} production and consequent inflammatory disease.

KW - signaling pathway

KW - LPS-induced TNF{alpha} production

KW - LPS

KW - monocytes

UR - http://dx.doi.org/10.1182/blood-2002-11-3596

U2 - 10.1182/blood-2002-11-3596

DO - 10.1182/blood-2002-11-3596

M3 - Article

VL - 102

SP - 2532

EP - 2540

JO - Blood

T2 - Blood

JF - Blood

SN - 0006-4971

ER -