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Infection and Immunity, March 2004, p. 1223-1229, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1223-1229.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Role of MyD88 in Diminished Tumor Necrosis Factor Alpha Production by Newborn Mononuclear Cells in Response to Lipopolysaccharide

Sen Rong Yan,1 Gefei Qing,1,{dagger} David M. Byers,1,2 Andrew W. Stadnyk,1,3 Walla Al-Hertani,1 and Robert Bortolussi1,3*

Departments of Pediatrics,1 Biochemistry and Molecular Biology,2 Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3J 3G9, Canada3

Received 17 June 2003/ Returned for modification 29 July 2003/ Accepted 19 November 2003

Human newborns are more susceptible than adults to infection by gram-negative bacteria. We hypothesized that this susceptibility may be associated with a decreased response by leukocytes to lipopolysaccharide (LPS). In this study, we compared LPS-induced secretion of tumor necrosis factor alpha (TNF-{alpha}) by mononuclear cells (MNC) from adult peripheral blood and newborn umbilical cord blood in vitro and attempted to determine the mechanisms involved in its regulation. At a high concentration of LPS (10 ng/ml) and in the presence of autologous plasma, MNC from adults and newborns secreted similar amounts of TNF-{alpha}. However, in the absence of plasma, MNC from newborns secreted significantly less TNF-{alpha} compared to MNC from adults. Moreover, at a low concentration of LPS (0.1 ng/ml) and in the presence of plasma, TNF-{alpha} secretion was significantly lower for newborn MNC compared to adult MNC. Adults and newborns had similar numbers of CD14 and Toll-like receptor 4 (TLR-4)-positive cells as measured by flow cytometry. However, the intensity of the CD14 marker was greater for adult than for newborn cells. Incubation of cells with LPS led to an increase in CD14 and TLR-4 intensity for adult cells but not for newborn cells. The effect of LPS stimulation of adult or newborn cells was similar for ERK, p38, and I{kappa}B{alpha} phosphorylation, as well as I{kappa}B{alpha} degradation. Finally, we assessed levels of the TLR-4 adapter protein, the myeloid differentiation antigen 88 (MyD88). We found a direct relation between adult and newborn TNF-{alpha} secretion and MyD88, which was significantly decreased in newborn monocytes. Since TLR-4 signals intracellularly through the adapter protein, MyD88, we hypothesize that MyD88-dependent factors are responsible for delayed and decreased TNF-{alpha} secretion in newborn monocytes.

* Corresponding author. Mailing address: IWK Health Centre, 5850 University Ave., Halifax, Nova Scotia B3J 3G9, Canada. Phone: (902) 470-8498. Fax: (902) 470-7217. E-mail: Robert.Bortolussi{at}Dal.ca.

Editor: F. C. Fang

{dagger} Present address: Department of Pathology, Health Science Centre, University of Manitoba, Winnipeg, Manitoba, Canada.

Infection and Immunity, March 2004, p. 1223-1229, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1223-1229.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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