HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Buhtoiarov, I. N. Articles by Rakhmilevich, A. L. Search for Related Content PubMed PubMed Citation Articles by Buhtoiarov, I. N. Articles by Rakhmilevich, A. L.

CD40 Ligation Activates Murine Macrophages via an IFN--Dependent Mechanism Resulting in Tumor Cell Destruction In Vitro ¹

Ilia N. Buhtoiarov^*, Hillary Lum^*, Gideon Berke, Donna M. Paulnock, Paul M. Sondel^*, and Alexander L. Rakhmilevich^2,*,

Departments of^* Human Oncology and Medical Microbiology and Immunology and UW Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53792; and Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

We have shown previously that agonistic anti-CD40 mAb induced T cell-independent antitumor effects in vivo. In this study, we investigated mechanisms of macrophage activation with anti-CD40 mAb treatment, assessed by the antitumor action of macrophages in vitro. Intraperitoneal injection of anti-CD40 mAb into C57BL/6 mice resulted in activation of peritoneal macrophages capable of suppressing B16 melanoma cell proliferation in vitro, an effect that was greatly enhanced by LPS and observed against several murine and human tumor cell lines. Anti-CD40 mAb also primed macrophages in vitro to mediate cytostatic effects in the presence of LPS. The tumoristatic effect of CD40 ligation-activated macrophages was associated with apoptosis and killing of tumor cells. Activation of macrophages by anti-CD40 mAb required endogenous IFN- because priming of macrophages by anti-CD40 mAb was abrogated in the presence of anti-IFN- mAb, as well as in IFN--knockout mice. Macrophages obtained either from C57BL/6 mice depleted of T and NK cells by Ab treatment, or from scid/beige mice, were still activated by anti-CD40 mAb to mediate cytostatic activity. These results argued against the role of NK and T cells as the sole source of exogenous IFN- for macrophage activation and suggested that anti-CD40 mAb-activated macrophages could produce IFN-. We confirmed this hypothesis by detecting intracytoplasmic IFN- in macrophages activated with anti-CD40 mAb in vivo or in vitro. IFN- production by macrophages was dependent on IL-12. Taken together, the results show that murine macrophages are activated directly by anti-CD40 mAb to secrete IFN- and mediate tumor cell destruction.

This article has been cited by other articles:

				I. M. Olazabal, N. B. Martin-Cofreces, M. Mittelbrunn, G. Martinez del Hoyo, B. Alarcon, and F. Sanchez-Madrid Activation Outcomes Induced in Naive CD8 T-Cells by Macrophages Primed via "Phagocytic" and Nonphagocytic Pathways Mol. Biol. Cell, February 1, 2008; 19(2): 701 - 710. [Abstract] [Full Text] [PDF]

				H. D. Lum, I. N. Buhtoiarov, B. E. Schmidt, G. Berke, D. M. Paulnock, P. M. Sondel, and A. L. Rakhmilevich In vivo CD40 ligation can induce T cell-independent antitumor effects that involve macrophages J. Leukoc. Biol., June 1, 2006; 79(6): 1181 - 1192. [Abstract] [Full Text] [PDF]

				I. N. Buhtoiarov, H. D. Lum, G. Berke, P. M. Sondel, and A. L. Rakhmilevich Synergistic Activation of Macrophages via CD40 and TLR9 Results in T Cell Independent Antitumor Effects J. Immunol., January 1, 2006; 176(1): 309 - 318. [Abstract] [Full Text] [PDF]