PRODUCTION OF IL-1 AND ITS RECEPTOR ANTAGONIST IS REGULATED DIFFERENTLY BY IFN-GAMMA AND IL-4 IN HUMAN MONOCYTES AND ALVEOLAR MACROPHAGES

Interleukin-4 (IL-4) has previously been found to downregulate interle ukin-1 (IL-1) production, but to upregulate the production of IL-1 rec eptor antagonist (Il-1ra) in human monocytes stimulated with lipopolys accharide (LPS). In the present study we wanted to determine whether t he production of IL-1ra in human monocytes and alveolar macrophages (A Ms) is regulated differently at the protein and messenger ribonucleic acid (mRNA) levels by Il-4 and interferon-gamma (IFN-gamma). AMs and m onocytes obtained from healthy donors by bronchoalveolar lavage and ce ntrifugal elutriation were stimulated with LPS in the presence or abse nce of IL-4 or IFN-gamma, and the expression of mRNA for IL-1 and IL-1 ra was measured by Northern blot analysis. The production of IL-l and IL-1ra was quantitated by enzyme immunoassays (EIAs). Spontaneous IL-1 ra production was seen in AMs after incubation for 4 h in medium alone , but not in blood monocytes, at both the protein and mRNA levels. The spontaneous expression of the IL-1ra gene in AMs was augmented by inc ubation with IL-4. Interleukiu-1 beta (IL-1 beta) production by LPS-st imulated AMs and monocytes was upregulated by IFN-gamma, but downregul ated by IL-4. Interestingly, when stimulated with LPS, IFN-gamma inhib ited IL-1ra production by monocytes, but up-regulated its production i n human AMs at the protein and mRNA levels. These results suggest that the production of IL-1 and IL-1ra by monocytemacrophages is regulated differently at the mRNA level, depending upon the balance between the production of Il-4 and IFN-gamma at the sites of T-cell/macrophage in teractions in the lung.