Posted by: Indonesian Children | August 15, 2009

Selective Impairment of TLR-Mediated Innate Immunity in Human Newborns: Neonatal Blood Plasma Reduces Monocyte TNF- Induction by Bacterial Lipopeptides, Lipopolysaccharide, and Imiquimod, but Preserves the Response to R-848

The Journal of Immunology, 2004, 173: 4627-4634.
Copyright © 2004 by The American Association of Immunologists

Selective Impairment of TLR-Mediated Innate Immunity in Human Newborns: Neonatal Blood Plasma Reduces Monocyte TNF- Induction by Bacterial Lipopeptides, Lipopolysaccharide, and Imiquimod, but Preserves the Response to R-848

FREE FULLTEXT

Ofer Levy2,*,,, Kol A. Zarember, Rene M. Roy*,, Colette Cywes*,, Paul J. Godowski and Michael R. Wessels*,,

* Channing Laboratory, Brigham and Women’s Hospital; Infectious Diseases, Children’s Hospital; and Harvard Medical School, Boston, MA 02115; and Department of Immunology, Genentech, South San Francisco, CA 94080

Newborns are at increased risk of overwhelming infection, yet the mechanisms underlying this susceptibility are incompletely defined. In this study we report a striking 1- to 3-log decrease in sensitivity of monocytes in human neonatal cord blood, compared with monocytes in adult peripheral blood, to the TNF–inducing effect of multiple TLR ligands, including bacterial lipopeptides (BLPs), LPS, and the imidazoquinoline compound, imiquimod. In marked contrast, TNF- release in response to R-848, a TLR ligand that is a congener of imiquimod, was equivalent in newborn and adult blood. Differences in ligand-induced TNF- release correlated with divergent ligand-induced changes in monocyte TNF- mRNA levels. Newborn and adult monocytes did not differ in basal mRNA or protein expression of TLRs or mRNA expression of functionally related molecules. Newborn monocytes demonstrated diminished LPS-induced, but equivalent R-848-induced, phosphorylation of p38 mitogen-activated protein kinase and altered BLP- and LPS-induced acute modulation of cognate receptors, suggesting that the mechanism accounting for the observed differences may be localized proximal to ligand recognition by surface TLRs. Remarkably, newborn plasma conferred substantially reduced BLP-, LPS-, and imiquimod-induced TNF- release on adult monocytes without any effect on R-848-induced TNF- release, reflecting differences in a plasma factor(s) distinct from soluble CD14. Impaired response to multiple TLR ligands may significantly contribute to immature neonatal immunity. Conversely, relative preservation of responses to R-848 may present unique opportunities for augmenting innate and acquired immunity in the human newborn.

 

 REFERENCE :

  1. Klein, J., J. Remington. 2001. Current concepts of infections of the fetus and newborn infant. J. Remington, and J. Klein, eds. Infectious Diseases of the Fetus and Newborn Infant 1. Saunders, Philadelphia.
  2. Zinkernagel, R. M.. 2001. Maternal antibodies, childhood infections, and autoimmune diseases. N. Engl. J. Med. 345:1331.[Free Full Text]
  3. Lewis, D. B., C. B. Wilson. 2001. Developmental immunology and role of host defenses in fetal and neonatal susceptibility to infection. J. Remington, and J. Klein, eds. Infectious Diseases of the Fetus and Newborn Infant 25. Saunders, Philadelphia.
  4. Hoffman, J., F. Kafatos, C. Janeway, R. Ezekowitz. 1999. Phylogenetic perspectives in innate immunity. Science 284:1313.[Abstract/Free Full Text]
  5. Landmann, R., B. Muller, W. Zimmerli. 2000. CD14, new aspects of ligand and signal diversity. Microbes Infect. 2:295.[Medline]
  6. Stanley, M. A.. 2002. Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential. Clin. Exp. Dermatol. 27:571.[Medline]
  7. Hemmi, H., T. Kaisho, O. Takeuchi, S. Sato, H. Sanjo, K. Hoshino, T. Horiuchi, H. Tomizawa, K. Takeda, S. Akira. 2002. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3:196.[Medline]
  8. Jurk, M., F. Heil, J. Vollmer, C. Schetter, A. M. Krieg, H. Wagner, G. Lipford, S. Bauer. 2002. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat. Immunol. 3:499.[Medline]
  9. Harandi, A. M., J. Sanchez, K. Eriksson, J. Holmgren. 2003. Recent developments in mucosal immunomodulatory adjuvants. Curr. Opin. Invest. Drugs 4:156.[Medline]
  10. Jones, T.. 2003. Resiquimod 3M. Curr. Opin. Invest. Drugs 4:214.[Medline]
  11. Ulevitch, R. J., P. S. Tobias. 1999. Recognition of Gram-negative bacteria and endotoxin by the innate immune system. Curr. Opin. Immunol. 11:19.[Medline]
  12. Vreugdenhil, A. C., C. H. Rousseau, T. Hartung, J. W. Greve, C. van’tVeer, W. A. Buurman. 2003. Lipopolysaccharide (LPS)-binding protein mediates LPS detoxification by chylomicrons. J. Immunol. 170:1399.[Abstract/Free Full Text]
  13. Kitchens, R. L., P. A. Thompson, S. Viriyakosol, G. E. O’Keefe, R. S. Munford. 2001. Plasma CD14 decreases monocyte responses to LPS by transferring cell-bound LPS to plasma lipoproteins. J. Clin. Invest. 108:485.[Medline]
  14. Akira, S.. 2003. Toll-like receptor signaling. J. Biol. Chem. 278:38105.[Free Full Text]
  15. Akira, S.. 2003. Mammalian Toll-like receptors. Curr. Opin. Immunol. 15:5.[Medline]
  16. Cohen, L., A. Haziot, D. R. Shen, X. Y. Lin, C. Sia, R. Harper, J. Silver, S. M. Goyert. 1995. CD14-independent responses to LPS require a serum factor that is absent from neonates. J. Immunol. 155:5337.[Abstract]
  17. Bessler, H., L. Komlos, I. Punsky, J. A. Ntambi, M. Bergman, R. Straussberg, L. Sirota. 2001. CD14 receptor expression and lipopolysaccharide-induced cytokine production in preterm and term neonates. Biol. Neonate 80:186.[Medline]
  18. Hirschfeld, M., Y. Ma, J. H. Weis, S. N. Vogel, J. J. Weis. 2000. Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine Toll-like receptor 2. J. Immunol. 165:618.[Abstract/Free Full Text]
  19. Yan, S. R., G. Qing, D. M. Byers, A. W. Stadnyk, W. Al-Hertani, R. Bortolussi. 2004. Role of MyD88 in diminished tumor necrosis factor {alpha} production by newborn mononuclear cells in response to lipopolysaccharide. Infect. Immun. 72:1223.[Abstract/Free Full Text]
  20. Biesert, L., W. Scheuer, W. G. Bessler. 1987. Interaction of mitogenic bacterial lipoprotein and a synthetic analogue with mouse lymphocytes: isolation and characterization of binding proteins. Eur. J. Biochem. 162:651.[Medline]
  21. Muhlradt, P. F., M. Kiess, H. Meyer, R. Sussmuth, G. Jung. 1997. Isolation, structure elucidation, and synthesis of a macrophage stimulatory lipopeptide from Mycoplasma fermentans acting at picomolar concentration. J. Exp. Med. 185:1951.[Abstract/Free Full Text]
  22. Levy, O., R. Jean-Jacques, C. Cywes, R. Sisson, K. A. Zarember, P. J. Godowski, J. Christianson, H. K. Guttormsen, M. C. Carroll, A. Nicholson-Weller, et al  2003. Critical role of the complement system in group B streptococcus-induced tumor necrosis factor {alpha} release. Infect. Immun. 71:6344.[Abstract/Free Full Text]
  23. Zarember, K. A., P. J. Godowski. 2002. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. [Published erratum appears in 2002 J. Immunol. 169:1136]. J. Immunol. 168:554.[Abstract/Free Full Text]
  24. Brown, M. A., P. Y. Rad, M. J. Halonen. 2003. Method of birth alters interferon-{gamma} and interleukin-12 production by cord blood mononuclear cells. Pediatr. Allergy Immunol. 14:106.[Medline]
  25. Uehara, A., S. Sugawara, R. Tamai, H. Takada. 2001. Contrasting responses of human gingival and colonic epithelial cells to lipopolysaccharides, lipoteichoic acids and peptidoglycans in the presence of soluble CD14. Med. Microbiol. Immunol. 189:185.[Medline]
  26. Holmlund, U., A. Hoglind, A. K. Larsson, C. Nilsson, E. Sverremark Ekstrom. 2003. CD14 and development of atopic disease at 2 years of age in children with atopic or non-atopic mothers. Clin. Exp. Allergy 33:455.[Medline]
  27. Bracci, R., G. Buonocore. 2003. Chorioamnionitis: a risk factor for fetal and neonatal morbidity. Biol. Neonate 83:85.[Medline]
  28. Massari, P., P. Henneke, Y. Ho, E. Latz, D. T. Golenbock, L. M. Wetzler. 2002. Cutting edge: immune stimulation by Neisserial porins is Toll-like receptor 2 and MyD88 dependent. J. Immunol. 168:1533.[Abstract/Free Full Text]
  29. Rharbaoui, F., B. Drabner, S. Borsutzky, U. Winckler, M. Morr, B. Ensoli, P. F. Muhlradt, C. A. Guzman. 2002. The mycoplasma-derived lipopeptide MALP-2 is a potent mucosal adjuvant. Eur. J. Immunol. 32:2857.[Medline]
  30. Sieling, P. A., W. Chung, B. T. Duong, P. J. Godowski, R. L. Modlin. 2003. Toll-like receptor 2 ligands as adjuvants for human Th1 responses. J. Immunol. 170:194.[Abstract/Free Full Text]
  31. Bernstein, D. I., R. L. Miller, C. J. Harrison. 1993. Adjuvant effects of imiquimod on a herpes simplex virus type 2 glycoprotein vaccine in guinea pigs. J. Infect. Dis. 167:731.[Medline]

Supported by

FIGHT AGAINST  AIDS, SAVE  INDONESIAN CHILDREN

YUDHASMARA FOUNDATION

JL TAMAN BENDUNGAN ASAHAN 5 JAKARTA PUSAT, JAKARTA INDONESIA 10210

PHONE :62 (021) 70081995 – 5703646

Email : judarwanto@gmail.com

https://childrenhivaids.wordpress.com/

 

Clinical and Editor in Chief :

DR WIDODO JUDARWANTO

email : judarwanto@gmail.com,

 

Copyright © 2009,  FIGHT AGAINST  AIDS, SAVE  INDONESIAN CHILDREN  Information Education Network. All rights reserved.


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Categories

%d bloggers like this: