MONOCYTE RESPONSE TO BACTERIAL TOXINS, EXPRESSION OF CELL-SURFACE RECEPTORS, AND RELEASE OF ANTIINFLAMMATORY CYTOKINES DURING SEPSIS

Exposure to endotoxin produces a state of macrophage hyporesponsivenes s on subsequent stimulation. Monocytes in patients with septic shock d emonstrate a similar hyporesponsiveness to endotoxin. The purpose of t his study was to examine whether this state of hyporesponsiveness exte nds to other inflammatory stimuli and the relationship of this state t o cell surface receptor expression and the release of anti-inflammator y cytokines. Twelve normal volunteers, 10 patients with severe sepsis, and 9 patients with septic shock were included in the study. Monocyte s from each subject were isolated and stimulated with lipopolysacchari de (LPS), staphylococcal enterotoxin B (SEE), and phorbol myristate ac etate (PMA). Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) were measured in the supernatants by enzyme-linked i mmunosorbent assay (ELISA). Serum revels of transforming growth factor -beta 1 (TGF-beta 1), prostaglandin E(2)(PGE(2)), and interleukin-10 ( IL-10) were also measured by ELISA. The expression of monocyte CD14 an d HLA-DR in whole blood were measured by flow cytometry. Patients with septic shock demonstrated significantly decreased TNF-alpha and IL-1 beta release as compared with normal subjects in response to LPS. In r esponse to SEE, patients with sepsis and patient with septic shock dem onstrated significantly decreased release of TNF-alpha and IL-1 beta. Significant decreases in TNF-alpha release were found in the patients with septic shock after PMA stimulation. There were no significant dif ferences in the monocyte response to the different stimuli between pat ients with gram-positive sepsis and gram-negative sepsis. HLA-DR expre ssion was significantly decreased in patients with septic shock (58 +/ - 9 fluorescence units (flU)) as compared with normal subjects (102 +/ - 14 flU) (p < 0.05). No differences in CD14 expression were observed. IL-10 levers were significantly increased in patients with sepsis (16 +/- 4 pg/ml) and in patients with septic shock (42 +/- 15 pg/ml) and were detectable in 1 normal subject. TGF-beta 1 levels were decreased in patients with septic shock (25 +/- 6 pg/ml) as compared with those in normal subjects (37 +/- 2 pg/ml)(p < 0.05). PGE(2) levels were sign ificantly increased in patients with septic shock and patients with se psis. These data are consistent with a more generalized monocyte hypor esponsiveness to bacterial toxins that may be related to altered cell surface receptor expression and the release of anti-inflammatory cytok ines.