In vitro production of IL 1β, IL 1α, TNF and IL 2 in healthy subjects: distribution, effect of cyclooxygenase inhibition and evidence of independent gene regulation

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Abstract
Numerous studies have reported altered in vitro cytokine production in various diseases. In the present study we used specific immunoassays to quantitate production of interleukin 1β (IL 1β), IL 1α, tumor necrosis factor (TNF) and IL 2 from human peripheral blood mononuclear cells (PBMC). The distribution of cell‐associated and secreted cytokines was studied in PBMC of 21 individuals; in response to lipopolysaccharide (LPS) the proportion of cell‐associated IL 1β ranged from 13% to 56%, for IL 1α 29% to 98%, and for TNF 2% to 17%. In a larger cohort of 32 subjects, the total amount of immunoreactive cytokines produced in response to LPS or phytohemagglutinin was normally distributed within the study group. Mean production of IL 1α in response to LPS was 10.1 ng/ml and exceeded production of IL 1β (5.6 ng/ml) and TNF (2.2 ng/ml). The distribution pattern was characterized by high intersubject variability extending over two orders of magnitude and the presence of high and low “producers”. Production of IL 1α and IL 1β correlated (R = 0.69). In contrast, production of IL 1β did not correlate with production of TNF or IL 2. Indomethacin present during stimulation of PBMC increased the amount of IL 1β produced and showed a high correlation (R = 0.83) compared to cultures without indomethacin. Thus, low production of IL 1β in certain subjects appears not to be due to inhibitable levels of cyclooxygenase products. In a retrospective study, PBMC from 12 subjects who had taken oral cyclooxygenase inhibitors during the preceding 7 days produced 43% more IL 1β than subjects who did not take these drugs (p < 0.05). These studies demonstrate that the amount of cytokine synthesized by PBMC (a) is regulated independently for IL 1, TNF and IL 2; (b) correlates for IL 1β and IL 1α; (c) is intrinsic for low and high “producers”, and (d) production of IL 1β increases with the use of oral cyclooxygenase inhibitors.