Polyanions macrophage activation

The mechanism of macrophage activation with polymer drugs such as synthetic polynucleotides and polyanionic polymers is not clearly understood. Two possibilities based on physiological responses are (1) the direct interaction or perturbation by the polymer drug with the cell cytoplasma membrane, and (2)... 

The uptake and location of pyran into the macrophage is of central importance in understanding the mechanism(s) by which these polyanionic polymers activate the macrophage to tumoricidal capacity. Very few studies have been addressed to this question with the exception of those performed by Pratten et al. [35]. 

For example, infection with a variety of bacteria will increase the effectiveness of the tumoricidal action of macrophages in vivo, A soluble lymphokine, produced by lymphocytes appears to be needed for this type of action. This poorly defined factor is called macrophage activating factor (MAF). In contrast certain interferon inducers, such as endotoxins and poly (I)-poly (C) can transform macrophages without the need for lymphocytes.24 Direct activation of macrophages by pyran copolymer and other polyanionic inducers without lymphocyte-derived MAF was also demonstrated.2 28 Since these inducers stimulate macrophages to produce interferon, and interferon activates macrophages, it is reasonable to think that interferon is the effective activator in these instances. 

The polyanions can function as chemical immunomodulators and produce a wide spectrum of effects on the immune system. It was reported that the polyanions have the capacity to activate macrophages, which may be related to their effects on the plasma membrane lipids, and to provide immuno-modulation through B-cell stimulation [8,9]. It was also observed that the antiviral, antibacterial, and antitumor activities of pyran copolymer may be mediated by the induction of interferon (IFN) production [10], macrophage activation [11], or stimulation of antibody-dependent cellular cytotoxicity... 

Polyanionic polymers can enter into biological functions by distribution throughout the host and they behave similar to proteins, glycoproteins and polynucleotides which modulate a number of biological responses related to the host defense mechanism. These are enhanced immune responses, and activation of the reticuloendothelial system (RES) macrophages. 

There has been much speculation concerning the mechanism of tionor Inhibition by these polyanlonlc systems. Many polyanions Induce Interferon production (22) and this fact has also been suggested as the source of the activity. More recently, it has been observed that DIVEMA is not cytotoxic to tumor cells (23) and that only those polymers that activated macrophages showed antlneoplastlc activity (24). Inhibition via macrophages Is believed to be the mode of action for DIVEMA (V) if not for all polyanlonlc polymers (16). 

The antiendotoxin activity of cationic peptides is also related to the above uptake mechanism. Endotoxin is in fact LPS, or more precisely the lipid A portion of LPS. As mentioned above, cationic peptides bind to polyanionic LPS (70.128,129). The binding is of high affinity and cooperative (70). This binding can neutralize the ability of LPS to induce TNF in macrophage cell lines or in a murine model, and it reduces endotoxin mortality in galactosamine-sei isitized mice (130,131). 

Further studies on the uptake and localization of other polyanionic polymers into cells should provide us with a clearer understanding of the mechanism(s) by which these agents activate the macrophage to become specifically cytotoxic to tumor cells. 

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