THE TUMOR NECROSIS FACTOR-INDUCING POTENCY OF LIPOPOLYSACCHARIDE AND URONIC-ACID POLYMERS IS INCREASED WHEN THEY ARE COVALENTLY-LINKED TO PARTICLES

Lipopolysaccharide (LPS) and polymers of the uronic acid family stimul ate monocytes to produce tumor necrosis factor (TNF), The TNF-inducing potency of these polysaccharides may depend on their supramolecular c onfiguration. In this study detoxified LPS and uronic acid polymers ha ve been covalently linked to particles which have been added to monocy tes under serum-free conditions, Reducing the size of mannuronan from 350,000 to 5,500 Da (M-blocks) led to a 10- to 100-fold reduction in T NF-inducing potency. However, covalently linking the M-blocks to monod isperse suspensions of magnetic particles increased the TNF-inducing p otency by up to 60,000-fold. Also, the TNF-inducing potency of glucuro nic acid polymers was increased when they were linked to particles, bu t no potentiation was observed with guluronic acid blocks covalently a ttached to particles. Furthermore, O chains of LPS (detoxified LPS) be came potent TNF inducers when they were presented to monocytes on a pa rticle surface, No activation of the LPS-responsive SW480 adenocarcino ma cells was found with detoxified LPS or M-block particles, suggestin g a preference for cells expressing CD14 and/or other membrane molecul es. The potentiating effects were not restricted to polymers attached to aminated magnetic particles. Of particular interest, we found that short blocks of mannuronan induced TNF production also when covalently linked to biodegradable, bovine serum albumin particles.