Mononuclear phagocytic cells contain low affinity receptors for IgE (Fc epsilon RII or CD23) which induce cellular activation in the presence of specific allergen. These studies were performed to quantify the expression by monocytes and alveolar macrophages of Fc epsilon RII in asthma and to determine biologic response modifiers that regulate Fc epsilon RII. Whereas 2.5 +/- 1.0% of the monocytes obtained from normal volunteers were Fc epsilon RII positive, this increased to 16.7 +/- 2.4% in asthma (p < 0.001). Stimulation of Fc epsilon RII expression on monocytes was shown to be an activity of IL-4 (24.5 +/- 5.9%), granulocyte-macrophage-CSF (28.1 +/- 5.2%), IFN-alpha (15.8 +/- 5.3%), IFN-gamma (10.4 +/- 3.7%), and macrophage-CSF (7.3 +/- 0.7%) but not of IL-2, IL-6, or TNF-alpha. Expression of Fc epsilon RII by these cytokines was associated with the induction of specific mRNA transcripts. Using Fc epsilon RII subtype specific primers in the polymerase chain reaction expansion of cDNA, cytokine-induced receptors were shown to be Fc epsilon RIIb. Alveolar macrophages from nonasthmatic subjects displayed minimal expression of Fc epsilon RII (3.2 +/- 1.2%); however, these receptors were present on 69.2 +/- 6.3% of asthmatic volunteers (p < 0.001). Induction of Fc epsilon RII appears specific for allergic asthma insofar as these receptors are also not expressed in subjects with interstitial lung disease (1.3 +/- 1.3%). As assessed by shift in mean fluorescence, instillation of allergen in the asthmatic's airway further up-regulated Fc epsilon RII on alveolar macrophages by 151 +/- 7%. Up-regulation of Fc epsilon RII in atopic individuals may therefore reflect allergen-induced exposure of mononuclear phagocytes to one or more of these cytokines. These studies suggest a mechanism by which an immunologic stimulus that leads to the production of these cytokines (e.g., allergen or viral infection) would contribute to the development or exacerbation of allergic disease.

Summary The IgE‐dependent activation of mononuclear phagocytic cells through their capacity to express low affinity IgE receptors (FcεRII) has been proposed as a mechanism for the development of airways inflammation in allergic asthma. This FcεRII expression leads to the IgE‐dependent production of the potent pro‐inflammatory cytokines IL‐1β and TNF‐α. Expression by monocytes of FcεRII is regulated by several cytokines including interleukin‐4, γ‐ and α‐interferons, and granulocyte‐macrophage and macrophage colony stimulating factors. An anti‐inflammatory effect of nedocromil on monocytes has been proposed as a possible mechanism for its anti‐asthma activity. We therefore investigated the capacity of nedocromil to modulate mononuclear phagocyte FcεRII expression and cytokine production. We used an anti‐FcεRII antibody and flow cytometric analysis to assess the capacity of nedocromil to modulate cytokine‐induced FcεRII expression in normals and asthmatics. Monocytes, THP‐1 monocyte leukaemia cells, and alveolar macrophages were exposed to varying concentrations of these cytokines for 48 hr at 37°C with or without the additional presence of nedocromil (1–10 μ m ) and the per cent of monocytes expressing FcεRII was determined. No changes in FcεRII expression were observed. Subsequently, we investigated the capacity of nedocromil to affect the capacity of IgE plus anti‐IgE complexes, allergen, and LPS (16 hr/37°C) to stimulate IL‐1β and IL‐6 production. No changes were observed when nedocromil was applied concomitant with the stimulus. However, pre‐treatment (30 min) with nedocromil was associated with a 59.5±5.6% inhibition of IL‐6 production stimulated by allergen and 34.5±5.1% by anti‐IgE. In conclusion, nedocromil does not modulate mononuclear phagocytic cell FcεRII expression but does suppress IgE‐dependent cytokine production. This may represent an important anti‐inflammatory action of nedocromil in the treatment of reactive obstructive airways disease.

Human serurn was found to contain an inhibitor of constitutive interleukin 1 (IL-1) production by human umbilical vein endothelial cells (ECs). Purification of the serum activity by anion exchange chromatography, molecular sieve HPLC, and hydroxyl apatite chromntography yielded material 82% pure with a molecular weight of 17 kDa by SDS-PAGE. Amino acid sequencing revealed the purified inhibitor to be transthyretin (TTR). a liver-derived protein. There was a 42.6% reduction in the production of spontaneous IL-1 activity in EC supernatants after coculture with 10μg/ml TTR. TTR was subsequently found by ELISA to inhibit LPS-stimulated IL-1 production by cells of the human monocytic leukemia line THP-1 by 47.1 ± 9.4%, whereas a less striking but still significant inhibition of monocyte-derived IL-1β production was also observed. Inhibition of IL-1 secretion correlated with increased IL-1 mRNA synthesis in both THP-1 cells and monocytes. Furthermore, TTR was associated with increased intracellulaf concentrations of IL-1β. These data suggest that TTR functions by inhibiting processing of newly synthesized peptide for secretion. This novel inhibitory effect of TTR on the production of IL-1 activity suggests a previously unrecognized endogenous antiinflammatory mediator.