Splenic PGE2-releasing macrophages regulate Th1 and Th2 immune responses in mice treated with heat-killed BCG.
Hosts infected with low doses of mycobacteria develop T helper cell type 1 (Th1) immunity, but at relatively higher doses, a switch to Th2 immunity occurs. Prostaglandin E2 (PGE2) is a proposed mediator of the Th1-to-Th2 shift of immune responses, and mycobacterial products induce PGE2-releasing macrophages (PGE2-MØ) in the mouse spleen in a dose-dependent manner. Splenic PGE2-M Ø from Balb/c mice, given 0.01 or 1 mg heat-killed (HK) Mycobacterium bovis bacillus Calmette-Guerin (BCG) intraperitoneally (i.p.), were characterized by the ex vivo release of PGE2 (>10 ng/10(6) cells), cytokine production, and expression of PGG/H synthase (PGHS)-1, PGHS-2, cytosolic PGE synthase (PGES), and microsomal PGES-1. At Day 14 after the treatment, mice treated with 1 mg, but not 0.01 mg, BCG had increased levels of PGHS-2+ PGE2-MØ, total serum immunoglobulin E (IgE), and serum IgG1 antibodies (Th2 responses) against heat shock protein 65 and purified protein derivative. Cultures of spleen cells isolated from these mice expressed interleukin (IL)-4 and IL-10 in recall responses. Treatment of mice receiving 1 mg BCG with NS-398 (a PGHS-2 inhibitor, 10 mg/kg i.p., daily) resulted in enhanced interferon-gamma (IFN-gamma) production with reduced IL-4 and IL-10 production in recall responses. This treatment also resulted in decreased total serum IgE levels. Treatment of C57Bl/6 mice with HK-BCG (0.5 mg dose) also induced a mixture of Th1 and Th2 responses, although IFN-gamma production was markedly increased, and IL-4 was decreased compared with Balb/c mice. Thus, our results indicate that by 14 days following treatment of mice with high doses of HK-BCG, splenic PGE2-MØ formation is associated with a PGHS-2-dependent shift from Th1-to-Th2 immune responses.
Shibata
Yoshimi
Y
Department of Biomedical Sciences, Florida Atlantic University, 777 Glades Rd., P.O. Box 3091, Boca Raton, FL 33431-0991, USA. yshibata@fau.edu
Henriksen
Ruth Ann
RA
Honda
Ikuro
I
Nakamura
Reiko M
RM
Myrvik
Quentin N
QN
D000818:Animals; D051545:Cyclooxygenase 1 / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000276:immunology; D016207:Cytokines / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015232:Dinoprostone / Q000276:immunology* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology*; D019746:Intramolecular Oxidoreductases / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000276:immunology; D000071876:Prostaglandin-E Synthases; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D014612:Vaccines / Q000276:immunology / Q000494:pharmacology
D016207:Cytokines; D008565:Membrane Proteins; D014612:Vaccines; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone