Interleukin-10 regulation in normal subjects and patients with asthma,☆☆,,★★

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Abstract

Interleukin-10 or cytokine synthesis inhibitory factor has important antiinflammatory activities in immune diseases. We speculated that diminished IL-10 production in asthma would permit the unopposed synthesis of proinflammatory cytokines, contributing to the development and severity of asthma. Our data demonstrate constitutive secretion of IL-10 into bronchoalveolar lavage (BAL) fluid of normal, nonasthmatic subjects (130 ± 61 pg/ml; n = 8). Asthmatic patients’ BAL fluid was characterized by diminished concentrations of IL-10 (9 ± 18 pg/ml; n = 8; p < 0.01 compared with that of normal subjects). By using the RNA-based polymerase chain reaction, we demonstrated that diminished IL-10 occurred as a result of inhibition of transcription. IL-10 transcription, but not protein, was observed at the time of the late asthmatic response. We speculate that the subsequent appearance of IL-10 protein could contribute to the resolution of the late asthmatic response. Similar to what was observed in the BAL fluid, peripheral blood mononuclear cells of patients with asthma demonstrated decreased spontaneous (0.01 ± 0.01 ng/ml—asthmatic and 0.09 ± 0.04 ng/ml—normal; p < 0.05) and stimulated (0.60 ± 0.22 ng/ml—asthmatic and 1.69 ± 0.49 ng/ml—normal; p < 0.05) IL-10 production compared with normal subjects. In support of the hypothesis that IL-10 mitigates the development of inflammation, we demonstrated that the addition of a neutralizing anti-IL-10 antibody to resting peripheral blood mononuclear cell cultures of normal subjects stimulated the spontaneous production of interferon-γ (10.4 ± 4.3 to 152.4 ± 23.6 ng/ml; p < 0.01). Finally, we reasoned that corticosteroids might exert at least part of their antiinflammatory activity through the induction of IL-10 secretion. However, methylprednisolone inhibited the lipopolysaccharide-stimulated production of IL-10 (2.34 ± 0.49 ng/ml IL-10 with lipopolysaccharide alone to 1.11 ± 0.38 ng/ml in the additional presence of 10-6 mol/L methylprednisolone; p < 0.05). (J ALLERGY CLIN IMMUNOL 1996;97:1288-96.)

Section snippets

Subjects

Assays were performed on cohorts of volunteers with asthma and normal control subjects (Table I, Table II). Normal volunteers were individuals who lacked a medical history consistent with atopic disease including asthma, allergic rhinitis, or eczema. Skin prick test responses to a Colorado allergen panel were negative, and at the time of study volunteers’ spirometry was normal. The asthmatic subjects met the criteria of the American Thoracic Society–American College of Chest Physicians for

IL-10 and IL-1β protein in BAL fluid

IL-10 protein concentration in BAL fluid was measured by an ELISA. Patient characteristics are summarized in Table I, Table II. IL-10 was readily measured in the BAL fluid of all of the normal subjects (130 ± 61 pg/ml; range, 41 to 211 pg/ml; n = 8). In contrast, only two of eight patients with asthma demonstrated IL-10 in the BAL fluid above the sensitivity of the ELISA, and even in these subjects, the concentration was lower than that observed in the normal subjects (9 ± 18 pg/ml; p < 0.01

DISCUSSION

Immune responses generated by cytokines are essential to the development of asthma. T lymphocyte–derived cytokines are required for the development of several phenotypic markers of asthma including IgE dysregulation (IL-4 and IL-1318, 19, 20), eosinophilia (IL-5, granulocyte-macrophage colony-stimulating factor, and IL-321, 22 ), mast cell proliferation (IL-3, IL-9, stem cell factor23, 24, 25), and enhanced histamine release (IL-3, RANTES, and monocyte chemotactic and activating factor26).

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    From the National Jewish Center for Immunology and Respiratory Medicine, University of Colorado Health Sciences Center, Denver.

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    Supported by National Institutes of Health grants AI32244, and HL36577.

    Reprint requests: Larry Borish, MD, Department of Medicine, National Center for Immunology and Respiratory Medicine, 1400 Jackson St., Denver, CO 80206.

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