We have previously shown that macrophages (Mphi) can be activated by CD40 ligation to become cytotoxic against tumor cells in vitro. Here we show that treatment of mice with agonistic anti-CD40 mAb (anti-CD40) induced up-regulation of intracellular TLR9 in Mphi and primed them to respond to CpG-containing oligodeoxynucleotides (CpG), resulting in synergistic activation. The synergy between anti-CD40 and CpG was evidenced by increased production of IFN-gamma, IL-12, TNF-alpha, and NO by Mphi, as well as by augmented apoptogenic effects of Mphi against tumor cells in vitro. The activation of cytotoxic Mphi after anti-CD40 plus CpG treatment was dependent on IFN-gamma but not TNF-alpha or NO, and did not require T cells and NK cells. Anti-CD40 and CpG also synergized in vivo in retardation of tumor growth in both immunocompetent and immunodeficient mice. Inactivation of Mphi in SCID/beige mice by silica treatment abrogated the antitumor effect. Taken together, our results show that Mphi can be activated via CD40/TLR9 ligation to kill tumor cells in vitro and inhibit tumor growth in vivo even in immunocompromised tumor-bearing hosts, indicating that this Mphi-based immunotherapeutic strategy may be appropriate for clinical testing.

Synergistic Activation of Macrophages via CD40 and TLR9 Results in T Cell Independent Antitumor Effects

CD14 is membrane-associating or free soluble glycoprotein which recognizes lipopolysaccharide (LPS) and is assumed to be involved in the onset of endotoxin shock. There are some reports suggesting the relationship between increased expression of CD14 in infectious or inflammatory diseases. However, little has been reported concerning the soluble CD14 (sCD14) level, especially in mice. In this study, we measured the plasma level of sCD14, TNF-alpha and IL-6 in the iota-carrageenan (CAR)-primed endotoxin shock model in addition to the D-galactosamine (D-galN)-primed endotoxin shock model mice. It was confirmed that all mice were dead within 12 h after a higher dose of LPS-treatment in both animal models. The level of TNF-alpha, IL-6 and sCD14 significantly increased in the CAR-primed endotoxin shock model mice. However, the D-galN-primed endotoxin shock model mice showed only a slight increment of TNF-alpha and IL-6 level, and sCD14 was below the detectable level. In the examination using several doses of LPS in CAR-primed model mice, IL-6 and sCD14 were increased dependent on the LPS dose, but TNF-alpha remained at an almost equal level at any dose of LPS in this study condition. In conclusion, the production of TNF-alpha, IL-6 and sCD14 was significantly enhanced in the CAR-primed model mice, compared to the D-galN-primed model mice. Therefore, these data indicate the possibility that the sCD14 level did not increase consistently, even under a fatal condition in endotoxin shock. Also, CAR-primed endotoxin shock would be an important experimental model to examine the elevation mechanisms for sCD14 and IL-6 production.

/pdf/increment-of-plasma-soluble-cd14-level-in-carrageenan-primed-2c25aa62q2.pdf

Increment of plasma soluble CD14 level in carrageenan-primed endotoxin shock model mice.

Sera of mice sensitized with bacteria and subsequently challenged with lipopolysaccha- ride promote hemorrhagic necrosis of tumors in vivo and display cytotoxic activity against tumor cells in vitro, which has been attributed to the induction of tumor necrosis factor (TNF). Here, we describe the induction of a previously unrecog- nized antitumor activity in such sera, which is dis- tinct from TNF but displays tumor-specific cyto- cidal activity in vitro as well as potent tumor-re- gressing activity in vivo. Biochemical analysis of this activity yielded a molecular mass of 150 kDa, closely resembling a novel tumoricidal factor of murine macrophages (M) termed MTC 170 (M tumor cytotoxin, approximate molecular mass 170 kDa), which we have previously pro- posed to constitute a major effector pathway for the destruction of tumor cells by activated M. J. Leukoc. Biol. 74: 1056-1063; 2003.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.0103042

TNF revisited: TNF‐independent antitumor activity in sera of mice sensitized with Propionibacterium acnes and challenged with lipopolysaccharide

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TNF revisited: TNF‐independent antitumor activity in sera of mice sensitized with Propionibacterium acnes and challenged with lipopolysaccharide