title: Endogenous pro- and anti-inflammatory cytokines differentially regulate an in vivo humoral response to Streptococcus pneumoniae.
abstract: 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.
authors.affiliation: Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
authors.forename: Abdul Q
authors.initials: AQ
authors.lastname: Khan
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.forename: Zheng-Qi
authors.initials: ZQ
authors.lastname: Wu
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
authors.forename: Clifford M
authors.initials: CM
authors.lastname: Snapper
mesh_terms: D018829:Adhesins, Bacterial; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000276:immunology; D007114:Immunization; D017578:Immunoglobulin Class Switching; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007375:Interleukin-1 / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008074:Lipoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010767:Phosphorylcholine / Q000276:immunology; D045331:Photosystem I Protein Complex; D013296:Streptococcus pneumoniae / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
chemical_list: D018829:Adhesins, Bacterial; D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; D006360:Heat-Shock Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D008074:Lipoproteins; D026901:Membrane Transport Proteins; D045331:Photosystem I Protein Complex; C085000:PsaA protein, Streptococcus; D014409:Tumor Necrosis Factor-alpha; C069816:phage shock protein, Bacteria; C051592:pneumococcal surface protein A; D010767:Phosphorylcholine; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma