GRAM-POSITIVE CELL-WALLS STIMULATE SYNTHESIS OF TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-6 BY HUMAN MONOCYTES

Purified cell walls representing a wide variety in teichoic acid and p eptidoglycan structure prepared from eight different gram-positive bac terial species induced the production of tumor necrosis factor alpha ( TNF-alpha) and interleukin-6 from human monocytes in the presence of 1 0% plasma or serum. Significant amounts of cytokines began to be produ ced at concentrations above 100 ng to 1 mu g of cell waifs per ml, wit h maximal production requiring 10 to 100 mu g of cell wall material pe r ml. In the absence of plasma, the cytokine-inducing capacity of cell wall preparations was lower by at least an order of magnitude. The se rum-derived cofactor was inactivated by heating at 90 degrees C for 30 min, suggesting that the activity is associated with a protein, bn th e other hand, replacement of normal with hypogammaglobulinemic plasma, inactivation of complement (at 56 degrees C), and blockade by the mon oclonal antibody MY4 of the CD14 receptors on monocytes did not inhibi t the production of TNF-alpha induced by whole cell walls. Cell walls also stimulated production of TNF-alpha in the presence of polymyxin B , and macrophages derived from the lipopolysaccharide-insensitive cell line of C3He/HeJ mice also produced this cytokine when stimulated by cell walls. Both peptidoglycan and the soluble glycan-teichoic acid co mponent prepared by an enzymatic method from the same wall preparation exhibited a serum-dependent induction of TNF-alpha from monocytes, wh ile stem peptides and disacharride peptides had only poor, if any, act ivity. Cell walls may contribute to the septic shock induced by gram-p ositive bacteria.