Splenic PGE2-releasing macrophages regulate Th1 and Th2 immune responses in mice treated with heat-killed BCG

Abstract

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.

Eicosanoid biosynthesis influences the virulence of Candida parapsilosis

“…Interestingly, the recognition of the C. albicans cell wall β-glucan by dectin-1 on the surface of macrophages enhances macrophage cytosolic phospholipase A2 activity and COX expression, thus promoting prostaglandin biosynthesis in the host [4,5]. Prostaglandin E 2 (PGE 2 ) is known to inhibit the Th1 response and promote Th2 immune responses [6,7]. Following C. albicans recognition, the induced PGE 2 production also enhances Th17 response [8].…”

Differential Macrophage Polarization in Male and Female BALB/c Mice Infected With Coxsackievirus B3 Defines Susceptibility to Viral Myocarditis

“…19 To determine the number of infiltrating macrophages per heart and to further analyze the phenotype of macrophages, the mononuclear cells were pooled from the hearts of 7 to 10 equivalently affected mice and F4/80 ϩ macrophages were isolated using purified antimouse F4/80 (BM8; eBioscience) in conjunction with goat anti-rat microbeads on a magnetic column (Miltenyi Biotec) as described previously. 20 This yields a population of Ͼ90% macrophages, assessed by fluorescence-activated cell-sorting (FACS) analysis using a FITC anti-F4/80 monoclonal antibody staining. And the number of macrophages per heart is calculated by dividing purified macrophage counts with the number of hearts pooled.…”

Persistent Inactivation of Macrophage Cyclooxygenase-2 in Mycobacterial Pulmonary Inflammation

“…Immunoregulatory effects of mycobacteria are demonstrated by increased resistance to infections and tumor growth, attenuation of the allergic response, and induction of autoimmune diseases in animal models (3)(4)(5)(6). The pleiotropic effects of mycobacteria could be mediated by induction in MØ of not only Th1-mediated microbicidal MØ responses but also pathogenic Th2, Th17, and Treg responses (7)(8)(9). The exact mechanisms regulating persistent mycobacterial inflammation in alveolar MØ still remain to be elucidated.…”