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Published online before print July 5, 2006

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(Journal of Leukocyte Biology. 2006;80:590-598.)
© 2006 by Society for Leukocyte Biology

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

Yoshimi Shibata^*,1, Jon Gabbard^*, Makiko Yamashita^*, Shoutaro Tsuji^*, Mike Smith, Akihito Nishiyama^*, Ruth Ann Henriksen and Quentin N. Myrvik

^* Department of Biomedical Sciences, Florida Atlantic University, Boca Raton; and
Department of Physiology, Brody School of Medicine at East Carolina University, Greenville, North Carolina; and
Caswell Beach, North Carolina

¹ Correspondence: Department of Biomedical Sciences, Florida Atlantic University, 777 Glades Rd., P.O. Box 3091, Boca Raton, FL 33431-0991. E-mail yshibata{at}fau.edu

Previous studies have shown that prostaglandin E₂ (PGE₂) release by splenic F4/80⁺ cyclooxygenase (COX)-2⁺ macrophages (MØ) isolated from mice, treated with mycobacterial components, plays a major role in the regulation of immune responses. However, splenic MØ, isolated from untreated mice and treated in vitro with lipopolysaccharide and interferon-, express COX-1 and COX-2 within 1 day but release only minimal amounts of PGE₂ following elicitation with calcium ionophore A23187. For further characterization of in vivo requirements for development of PGE₂-releasing MØ (PGE₂-MØ), C57Bl/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 MØ of both mouse strains. However, PGE₂ biosynthesis by these MØ 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 MØ 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 PGE₂-MØ 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 1 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⁺ MØ may be responsible for the increased PGE₂ production.

Key Words: PGE₂ • releasing macrophage • F4/80⁺ • GFP • chimera

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