T cell-replacing factor for glucocorticosteroid-induced immunoglobulin production. A unique steroid-dependent cytokine.

Abstract

Glucocorticosteroids (GCS) added to otherwise unstimulated cultures of human peripheral blood mononuclear cells (PBMC) induce the synthesis and secretion of all classes of immunoglobulin. The magnitude of this response is similar to that seen with other polyclonal B cell activators such as pokeweed mitogen (PWM), and like that of PWM, the steroid effect is dependent on both T cells and monocytes. To determine the cellular target for GCS in these cultures, separated populations of T cells and non-T cells were preincubated with steroids and then recombined. No immunoglobulin was produced in any of these preincubation experiments. As a different approach to this question, supernatants were collected from various cell populations following stimulation with PWM, concanavalin A (Con A), phytohemagglutinin (PHA), alloantigens, or GCS. These supernatants were tested for their effects on GCS-induced Ig production by B cells. Supernatants from 3-d cultures of unstimulated, as well as GCS-treated, PBMC contained a T cell-replacing factor that permitted T-depleted PBMC to produce Ig upon steroid stimulation. This supernatant factor (TRF-S) could be produced in the absence of steroid stimulation, but both the factor and GCS were necessary for the induction of Ig synthesis. Production of the TRF-S required the presence of both T cells and adherent cells in culture and was found in the highest concentrations at 3-4 d of culture. Supernatants from cultures stimulated with PWM, PHA, Con A, and alloantigens did not contain detectable TRF-S activity, and TRF-S was unable to replace helper T cells for PWM-induced Ig production. TRF-S required the presence of adherent cells in the T cell-depleted responder population for its action. Further, it was effective in inducing Ig production along with GCS in the presence of a sufficient concentration of cyclosporin A to block all T cell helper activity for primary responses of PBMC to PWM or GCS. TRF-S was inactivated by trypsin treatment, heating to 56 degrees C, freezing, lyophilization, and storage at 4 degrees C for greater than 3 wk. Its molecular weight is probably 10,000 daltons or more, since TRF-S activity is not rapidly dialyzable. These experiments indicate that GCS-induced Ig production by human B cells does not require the presence of intact T cells in the cultures and therefore the steroids are not exerting their influence directly on T suppressor or T helper cells. Furthermore, they demonstrate a previously unrecognized cytokine that induces the differentiation of human B cells to Ig production in the presence of GCS.

Glucocorticoids increase the synthesis of immunoglobulin E by interleukin 4-stimulated human lymphocytes.

“…The augmenting effect of HC on IgE synthesis by IL-4-stimulated cells is not isotype-specific, and moreover in the absence of IL-4, HC does not induce IgE synthesis whereas it increases the production ofthe other isotypes. The latter phenomenon has been extensively analyzed and shown to involve both cellular interactions between monocytes, CD4+ T cells and B lymphocytes as well as the release of T cell-derived soluble factors induced by GCs (30,31). The mechanisms leading to the synthesis of IgE after the addition ofIL-4 to cultures ofhuman PBMCs have been extensively analyzed.…”

Detection of Anti-HBc IgM Following Prednisone Treatment in Patients with Chronic Active Hepatitis B Virus Infection

“…They suggest that a preexisting chronic inflammatory process results in the activation of monocytes/macrophages and elevation of physiologic levels of glucocorti-costeroids. This may create a condition whereby helper T-cells are selectively protected from steroid induced suppression by factors similar to IL-1 or by a unique steroid dependent cytokine secreted by activated macrophages described by Orson et al (22). When prednisone therapy is terminated, redistribution of OKT8+ (suppressor/cytotoxic), IgG Fc and IgM Fc receptor-positive lymphocyte subsets is observed.…”

Immunoglobulin production in vitro in major depression: A pilot study on the modulating action of endogenous cortisol

“…In the pokeweed mitogen (PWM)-~:lriven Ig synthesis by cultured lymphocytes, physiological as well as supraphysiological doses of glucocorticoids have an enhancing property, provided that they are present at the beginning of the culture (Fauci et al 1977;Cooper et al 1979;Brieva et al 1983). In addition, Ig production can be induced by glucocorticoids in lymphocytes cultured in vitro in the presence of fetal calf serum (FCS), without the addition of any other mitogen (Smith et al 1972;Grayson et al 1981 ;Orson et al 1983). FCS seems to be required for this stimulating effect (Sierakowski and Goodwin 1988).…”