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

• Published in: Journal of leukocyte biology Vol. 80; no. 3; pp. 590 - 598
• Main Authors: Shibata, Yoshimi, Gabbard, Jon, Yamashita, Makiko, Tsuji, Shoutaro, Smith, Mike, Nishiyama, Akihito, Henriksen, Ruth Ann, Myrvik, Quentin N.
• Format: Journal Article
• Language: English
• Published: United States Society for Leukocyte Biology 01.09.2006
• Subjects: Animals; BCG Vaccine - administration & dosage; BCG Vaccine - immunology; Bone Marrow Cells - immunology; Cell-Free System - metabolism; Chimera; Cyclooxygenase 2 - biosynthesis; Cyclooxygenase 2 - drug effects; Cyclooxygenase 2 - immunology; Dinoprostone - biosynthesis; Dinoprostone - immunology; F4/80; Female; GFP; Interleukin-10 - deficiency; Interleukin-10 - immunology; Macrophages - drug effects; Macrophages - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; PGE2; releasing macrophage; Spleen - cytology; Spleen - drug effects; Spleen - immunology; Structure-Activity Relationship
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.1205737

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‐γ, 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.