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Infection and Immunity, February 2002, p. 749-761, Vol. 70, No. 2
0019-9567/01/$04.00+0     DOI: 70.2.749-761.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Endogenous Pro- and Anti-Inflammatory Cytokines Differentially Regulate an In Vivo Humoral Response to Streptococcus pneumoniae

Abdul Q. Khan,1 Yi Shen,1 Zheng-Qi Wu,1 Thomas A. Wynn,2 and Clifford M. Snapper1*

Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814,1 Laboratory of Parasitic Diseases, National Institutes of Health, Bethesda, Maryland 208922

Received 18 September 2001/ Returned for modification 24 October 2001/ Accepted 6 November 2001

Proinflammatory cytokines play a critical role in innate host defense against extracellular bacteria. However, little is known regarding the effects of these cytokines on the adaptive humoral response. Mice injected with a neutralizing anti-tumor necrosis factor alpha (TNF-{alpha}) monoclonal antibody (MAb) at the time of primary immunization with intact Streptococcus pneumoniae (strain R36A) showed a substantial reduction in both the primary immunoglobulin G (IgG) response specific for the cell wall protein, pneumococcal surface protein A (PspA), as well as in the development of PspA-specific memory. In contrast, anti-TNF-{alpha} MAb injected only at the time of secondary immunization with R36A failed to alter the boosted anti-PspA response. TNF-{alpha} was required only within the first 48 to 72 h after primary immunization with R36A and was induced both by non-B and non-T cells and by lymphoid cells, within 2 to 6 h after immunization, with levels returning to normal by 24 h. Thus, the early innate release of TNF-{alpha} was critical for optimal stimulation of the subsequent adaptive humoral response to R36A. Additional proinflammatory (interleukin 1 [IL-1], IL-6, IL-12, and gamma interferon [IFN-{gamma}]) as well as anti-inflammatory (IL-4 and IL-10) cytokines were also transiently induced. Mice genetically deficient in IL-6, IFN-{gamma}, or IL-12 also showed a reduced IgG anti-PspA response of all IgG isotypes. In contrast, IL-4-/- and IL-10-/- mice immunized with R36A showed a significant elevation in the IgG anti-PspA response, except that there was decreased IgG1 in IL-4-/- mice. In this regard, a marked enhancement in the induction of proinflammatory cytokines was observed in the absence of IL-10, relative to controls. Ig isotype titers specific for the phosphorycholine determinant of C-polysaccharide were similarly regulated, but to a much more modest degree. These data suggest that proinflammatory and anti-inflammatory cytokines differentially regulate an in vivo protein- and polysaccharide-specific Ig response to an extracellular bacteria.

* Corresponding author. Mailing address: Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814. Phone: (301) 295-3490. Fax: (301) 295-1640. E-mail: csnapper{at}usuhs.mil.

Editor: E. I. Tuomanen

Infection and Immunity, February 2002, p. 749-761, Vol. 70, No. 2
0019-9567/01/$04.00+0     DOI: 70.2.749-761.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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