Bone marrow colony-stimulating factor and tumor resistance-enhancing activity of postendotoxin mouse sera

Abstract

The passive transfer of postendotoxin mouse serum could enhance nonspecific resistance to the development of TA3-Ha transplantable ascites tumor in mice. The postendotoxin serum was not directly cytotoxic to TA3-Ha tumor cells in vitro, nor did it contain significant amounts of residual endotoxin, but it was rich in colony-stimulating factors (CSFs). High-titer CSF serum could be induced by endotoxic lipopolysaccharide (LPS). Nonendotoxic, lipid-free, and polysaccharide-rich hydrolytic breakdown product of LPS (called PS) was less potent but still active in CSF induction. There was a correlation between the level of CSF stimulation and the capacity of the sera to transfer tumor resistance (TUR) Those LPS preparations that had the highest CSF-inducing capacity were the most potent in TUR enhancement. Suppression of CSF production by treatment with theophylline or epinephrine, enhancers of cyclic AMP/cyclic GMP ratios, lowered the enhancement of TUR by endotoxic LPS. The infection of serum donor mice with bacillus Calmette-Guerin (BCG) 18 days prior to LPS treatment gave the highest serum CSF levels and the most potent TUR-inducing serum preparation. Even more notable was the finding that the nontoxic PS preparation could replace toxic LPS in the above BCG-LPS system. The serum harvested from BCG-infected mice 2 hr after PS injection was similarly effective in the passive transfer of TUB. Endotoxin has been demonstrated to produce antitumor effects in two systems. Some tumors can undergo hemorrhage and necrosis after injection of endotoxin, as shown by Shear and associates (1-3). The effect of purified and detoxified endotoxins on sarcoma 37 has been investigated in our laboratories (4). Our earlier findings as well as the findings of others indicate that endotoxin does not act directly on the tumor cells in the hemorrhagic necrosis system. We assumed in 1971 that the antitumor effects were mediated by certain humoral factors produced by endotoxin injection (4). We also reported that pretreatment with endotoxin enhances the nonspecific resistance of mice to challenge with the

Role of lipid a in the production of tumor necrosis factor and differences in antitumor activity between tumor necrosis factor and lipopolysaccharide.

“…As mentioned above, Butler et al (1978) reported that antitumor factor in post-endotoxin serum can be induced not only by LIPS but also by its non-toxic polysaccharide-rich subfration.…”

“…or P. aches has been used as the first stimulator in mice and LPS at the second with an interval of more than one week. Hepatos- Effect of galactosamine on the susceptibility of TNF or LPS plenomegaly is generally observed in mice treated with one of the first stimulating agents and provides a good indication that the mice are producing high TNF titers (Butler et al 1978 ;Satomi et al 1981). However, a genetic predisposition to LPS sensitivity (Mannel et al 1979), especially after the mice have received the first stimulator, seems to be a more important factor deciding the fate of the subsequent TNF production (Suter et al 1958).…”

“…If the non-toxic portion of LPS displays eliciting activity for TNF production, TNF could be produced in tumorbearing hosts. Previously, Butler et al (1978) reported in their passive transfer experiments conducted with post-endotoxin serum, that a nonspecific resistant factor against TA3-Ha ascites tumor can be induced not only by LPS but also by its non-toxic polysaccharide-rich subfraction. In the present study, lipid A and…”

“…For the production of TNF, both priming agents and eliciting agents are necessary (Carswell et al 1975 ; Butler et al 1978). The LPS which is used as an eliciting agent has a lethal effect in the host.…”

Possible role of endotoxin in mediating host resistance

“…The majority of host responses, however, is mediated by soluble factors elicited upon the LPS stimulus. The production of interferon, colony stimulating factor and lymphocyte activating factor -to mention just a few activities -can be demonstrated after LPS application to the appropriate host [2][3][4]. Such mediators have been subject of intensive modern research and they have been shown to modulate immune reactions by acting on the immune system in sometimes complex ways (for review see [5,6]).…”