EFFECT OF CYTOKINES IN HOST DEFENSE AND INFLAMMATION

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The kinetics of the appearance of cytokines and mediators of inflammation was determined in normal subjects and in selected patients with abnormal host defense. For this study a model of inflammation in the skin was employed using a blister device. Previously we showed that in normal subjects C5a and LTB4 appeared within 3 h of raising blisters, I1-8 and I1-6 appeared from 8 through 24 h and IL1-B, GM-CSF and TNF-alpha appeared from 12 to 24 h. Recently we have shown that "resting" exudate neutrophils are capable of secreting about ten times more I1-8 than "resting" peripheral blood neutrophils. When peripheral blood neutrophils are stimulated, synthesis of I1-8 is induced and I1-8 is stored in a membrane associated compartment that is readily mobilized and secreted. Exudate neutrophils also produce I1-6 and TNF-alpha. Studies in patients with chronic granulomatous disease revealed normal mediator accumulation in these patients. In contrast, patients with the hyperimmunoglobulin E-recurrent infection (HIE) syndrome had about ten- fold increased TNF-alpha accumulation in the blister fluid. The increased TNF-alpha was restricted to the local inflammatory response since in related studies, in which a preparation of the lipid A component of E. coli endotoxin was administered intravenously to normal volunteers and HIE subjects, normal increases in TNF-alpha, I1-8 and I1-6 in the circulation in HIE subjects was observed. Abnormal regulation of TNF-` at local inflammatory sites may have important implications in the pathogenesis of the post infectious complications seen in HIE such as bronchiectasis and bronchopleural fistula formation following pneumonia. In related studies, intravenous endotoxin was administered to normal volunteers and the kinetics of mediator production was followed in the subjects' sera. Increased I1-8 and TNF-alpha was temporally associated with the neutropenic and febrile phases of the response; increased soluble TNF-alpha receptor paralled increased total circulating TNF- alpha. Increases in I1-6 and G-CSF and small increases in GM-CSF correlated with the neutrophilia and increased lactoferrin observed following intravenous endotoxin. Changes in plasma I1-1, I1-2 and I1-4 were not detected following intravenous endotoxin.