Heat-killed BCG induces biphasic cyclooxygenase 2(+) splenic macrophage formation - role of IL-10 and bone marrow precursors

Previous studies have shown that prostaglandin E-2 (PGE(2)) release by splenic F4/80(+) cyclooxygenase (COX)-2(+) macrophages (M circle divide) isolated from mice, treated with mycobacterial components, plays a major role in the regulation of immune responses. However, splenic M circle divide, isolated from untreated mice and treated in vitro with lipopolysaccharide and interferon-gamma, express COX-1 and COX-2 within I day but release only minimal amounts of PGE2 following elicitation with calcium ionophore A23187. For further characterization of in vivo requirements for development of PGE(2)-releasing M circle divide (PGE(2)-M circle divide), C57B1/6 [wild-type (WT)], and interleukin (IL)-10-deficient (IL-10(-/-)) mice were treated intraperitoneally with heat-killed Mycobacterium bovis bacillus Calmette-Guerin (HK-BCG). One day following injection, COX-2 was induced in splenic M circle divide of both mouse strains. However, PGE2 biosynthesis by these M circle divide was not increased. Thus, expression of COX-2 is not sufficient to induce PGE2 production in vivo or in vitro. In sharp contrast, 14 days after HK-BCG treatment, PGE2 release by COX-2(+) splenic M circle divide increased as much as sevenfold, and a greater increase was seen in IL-10-/- cells than in WT cells. To further determine whether the 14-day splenic PGE(2)-M circle divide could be derived from bone marrow precursors, we established a chimera in which bone marrow cells were transfused from green fluorescent protein (GFP)-transgenic donors to WT mice. Donors and recipients were treated with HK-BCG simultaneously, and marrow transfusion was performed on Days I and 2. On Day 14 after BCG treatment, a significant number of spleen cells coexpressed COX-2 and GFP, indicating that bone marrow-derived COX-2+ M circle divide may be responsible for the increased PGE(2) production.