Production of IL-1 and its receptor antagonist is regulated differently by IFN-γ and IL-4 in human monocytes and alveolar macrophages

Abstract

Interleukin-4 (IL-4) has previously been found to downregulate interleukin-1 IL-1) production, but to upregulate the production of IL-1 receptor antagonist (TL-1ra) in human monocytes stimulated with lipopolysaccharide (LPS). In the present study we wanted to determine whether the production of IL-1ra in human monocytes and alveolar macrophages (AMs) is regulated differently at the protein and messenger ribonucleic acid (mRNA) levels by IL-4 and interferon-γ (IFN-γ). AMs and monocytes obtained from healthy donors by bronchoalveolar lavage and centrifugal elutriation were stimulated with LPS in the presence or absence of IL4 or IFN-γ, and the expression of mRNA for IL-1 and IL-1ra was measured by Northern blot analysis. The production of IL-1 and IL-1ra was quantitated by enzyme immunoassays (EIAs). Spontaneous IL-1ra 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 incubation with IL-4. Interleukin-1β (IL-1β) production by LPS-stimulated AMs and monocytes was upregulated by IFN-γ, but downregulated by IL-4. Interestingly, when stimulated with LPS, IFN-γ inhibited IL-1ra product!on by monocytes, but up regulated its production in human AMs at the protein and mRNA levels. These results suggest that the production of IL-1 and IL-1ra by monocyte-macrophages is regulated differently at the mRNA level, depending upon the balance between the production of IL-4 and IFN-γ at the sites of T-cell/macrophage interactions in the lung.