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Published online before print July 5, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1205737

Received for publication December 15, 2005.
Revised April 7, 2006.
Accepted for publication May 2, 2006.

Article

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

Yoshimi Shibata ^*@, Jon Gabbard ^*, Makiko Yamashita Tsuji ^*, 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, and Southport

^@ To whom correspondence should be addressed. E-mail: yshibata{at}fau.edu.

	Abstract

Previous studies have shown that prostaglandin E₂ (PGE₂) release by splenic F4/80⁺ cyclooxygenase (COX)-2⁺ macrophages (M) isolated from mice, treated with mycobacterial components, plays a major role in the regulation of immune responses. However, splenic M, 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, in vivo requirements for development of PGE₂-releasing M (PGE₂-M), 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 M of both mouse strains. However, PGE₂ biosynthesis by these M 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 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-M 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⁺ M may be responsible for the increased PGE₂ production.

Key Words: COX-2 • spleen • PGE₂

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