CYTOKINE PRODUCTION BY NORMAL HUMAN MONOCYTES - INTER-SUBJECT VARIATION AND RELATIONSHIP TO AN IL-1 RECEPTOR ANTAGONIST (IL-1RA) GENE POLYMORPHISM

Monocytes from different individuals show variable cytokine production in response to a variety of stimuli. We wished to determine the sets of conditions (cytokine combinations) that would enable us to demonstr ate stable inter-individual differences in the production of IL-1 alph a, IL-1 beta, IL-1Ra, IL-6 and tumour necrosis factor-alpha (TNF-alpha ) by monocytes. We assessed the ability of a number of recombinant hum an cytokines (granulocyte-macrophage colony-stimulating factor (GM-CSF ), interferon-gamma (IFN-gamma), TNF-alpha, IL-4, IL-6, transforming g rowth factor-beta (TGF-beta), IL-10 and IL-1Ra)) to stimulate or inhib it the production of one or more of these monocyte products. CM-CSF wa s found to stimulate the production of all five of these cytokines in a highly reproducible manner. TNF-alpha also up-regulated production o f IL-1 alpha, IL-1 beta, IL-1Ra and IL-6 by monocytes, but the variabi lity in the results of cells cultured from the same individuals on dif ferent occasions was greater. Other cytokines either stimulated produc tion of only some of the five cytokine products tested, or stimulated the production of some cytokine products while inhibiting production o f others. This was especially evident when cytokines were used in comb ination with GM-CSF: IFN-gamma down-regulated production of IL-1Ra whi le up-regulating the production of IL-1 alpha/beta, IL-6 and TNF-alpha , while IL-4 had the exact opposite effect. Polymorphisms in regions o f cytokine genes that affect transcription may account for some of the interindividual variation in cytokine production. We have shown that a stable estimate of cytokine production phenotype can be obtained whe n monocytes collected on at least two separate occasions are stimulate d by GM-CSF in vitro. We have looked for a relationship between IL-1 p roduction and an 86-bp variable repeat polymorphism in intron 2 of the IL-1Ra gene. A less common allele of this polymorphism (allele 2) was associated with increased production of IL-1Ra protein, and also redu ced production of IL-1 alpha protein by monocytes.