Pharmacological inhibition of interleukin-1 activity on T cells by hydrocortisone, cyclosporine, prostaglandins, and cyclic nucleotides

Tracey, Daniel E.; Hardee, Marilyn M.; Richard, Karen A.; Paslay, Jeff W.

doi:10.1016/0162-3109(88)90042-2

Cited by 13 publications

(3 citation statements)

References 35 publications

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“…The mechanism of corticosteroid-induced immunosuppression in vivo is poorly understood and we realize that caution must be exercised when interpreting the results obtained after culturing lymphocytes with steroids, as these do not guarantee that the same biological effect occurs after administration in vivo [10,29]. In the body, most corticosteroids are eliminated quickly and, therefore, steadystate levels are not achieved and their biological effects change continuously at the usual daily dosages.~ Culture studies have provided a wealth of information and we now know that pharmacological concentrations of glucocorticosteroids affect immune functions by (a) decreasing expression of histocompatibility antigens on antigenprocessing cells [15]; (b) preventing destruction of microorganisms ingested by macrophages [36]; (c) hindering interleukin-1 and tumor necrosis factor production by macrophages [39,41,43]; (d) inhibiting production of lymphokines including IL-2 and IFN-? [2,23,27]; (e) inhibiting NK cytotoxic activity [16,31]; and (f) depressing the proliferative response of T cells to both mitogenic and antigenic stimuli [27].…”

Section: Discussionmentioning

confidence: 99%

Corticosteroids inhibit the generation of lymphokine-activated killer activity in vitro

McVicar

Merchant

et al. 1989

Cancer Immunol Immunother

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In phase-I clinical trials of adoptive immunotherapy using lymphokine-activated killer (LAK) cells plus recombinant interleukin-2 (rIL-2) (Cetus) for the treatment of malignant glioma, we observed that blood mononuclear cells (MNC) from patients dependent on dexamethasone for management of cerebral edema produced substantially less LAK activity as compared to MNC of normal blood donors or glioma patients not receiving steroid therapy. Therefore, we examined the in vitro effects, brought about by therapeutically attainable concentrations of various corticosteroids, on the proliferative response, production of gamma interferon (IFN-gamma), and induction of LAK activity from blood MNC of normal donors. Incubation in media containing rIL-2 (1000 U/ml) with either dexamethasone, hydrocortisone, methylprednisolone, or prednisolone profoundly affected all of these parameters. First, while 0.01 micrograms/ml of either dexamethasone or hydrocortisone caused a slight enhancement of the mitogenic response of lymphocytes to phytohemagglutinin, a dose-dependent decline occurred as concentrations increased to 10 micrograms/ml. The addition of prednisolone and methylprednisolone elicited a dose-dependent inhibition of lymphocyte proliferation over the entire concentration range tested. At 0.1 microgram/ml or higher, dexamethasone, hydrocortisone, methylprednisolone and prednisolone significantly (P less than 0.02) inhibited the production of IFN-gamma: respectively 18.9%, 4.4%, 2.2%, and 12.3% of the IFN-gamma produced by MNC in the absence of steroids. All four corticosteroids inhibited the induction of LAK activity. Compared to MNC that had been incubated with 1000 U/ml rIL-2 alone, MNC cultured with rIL-2 and 10 micrograms/ml either dexamethasone or prednisolone demonstrated significantly lower cytotoxicity (P less than 0.05) for the natural-killer-cell-resistant cell line, Daudi. Culturing MNC with hydrocortisone had a more dramatic result, causing a significant decline (P less than 0.01) in lytic activity at both 1.0 micrograms/ml and 10 micrograms/ml, while incubation with methylprednisolone produced a significant drop (P less than 0.02) in LAK-mediated cytotoxicity at 0.1 micrograms/ml as well as 1.0 micrograms/ml and 10 micrograms/ml. When cytotoxicity was expressed as lytic units per million effectors, a dose-response decline in lytic activity was once again apparent, with hydrocortisone, methylprednisolone and prednisolone showing significant inhibition (P less than 0.05) at both 1.0 micrograms/ml and 10 micrograms/ml and dexamethasone at 10 micrograms/ml (P less than 0.01). These results indicate that corticosteroids commonly used in the management of cere

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Section: Discussionmentioning

confidence: 99%

Corticosteroids inhibit the generation of lymphokine-activated killer activity in vitro

McVicar

Merchant

et al. 1989

Cancer Immunol Immunother

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“…An increase in intracellular adenosine 3':5'-cyclic monophosphate (cyclic AMP) can also suppress lymphocyte proliferation and effector functions by inhibiting early steps of their activation (Bourne et al, 1974;Kammer, 1988). For example both cyclic AMP elevation and glucocorticoids inhibit expression of interleukin-2 (Northrop et al, 1992;Anastassiou et al, 1992) and interleukin-2 receptors (Tracey et al, 1988;Anastassiou et al, 1992) at a transcriptional level. In non-lymphoid tissues, glucocorticoids can enhance cyclic AMP formation (Malbon et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Sensitization by dexamethasone of lymphocyte cyclic AMP formation: evidence for increased function of the adenylyl cyclase catalyst

Michel

Knapp

Ratjen

1994

British J Pharmacology

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1 Glucocorticoids and elevations of intracellular adenosine 3':5'-cyclic monophosphate (cyclic AMP) may affect lymphocyte activation, proliferation and effector functions in similar ways. Therefore, we have investigated the effects of the glucorticoid, dexamethasone, on human lymphocyte cyclic AMP formation.2 Treatment of resting human lymphocytes with the glucocorticoid, dexamethasone, sensitized prostaglandin E2-stimulated cyclic AMP accumulation in a time-and concentration-dependent manner. 3 In membranes of lymphocytes treated for 24h with 100nM dexamethasone, maximal adenylyl cyclase activity stimulated by prostaglandin E2, isoprenaline, guanosine 5'-triphosphate (GTP), forskolin and MnCl2 was significantly enhanced; the ECQ0 for these agents was not significantly altered.4 132-Adrenoceptor density, immunodetectable a-subunits of the G-proteins G, and Gi, and pertussis toxin-substrates were not significantly altered by dexamethasone treatment. 5 In dexamethasone-treated lymphocytes, prostaglandin E2-mediated inhibition of concanavalin Ainduced Ca2' elevations was doubled compared to control cells.6 Based on these data and the observation that enhancement of forskolin-and MnCl2-stimulated adenylyl cyclase activity could quantitatively account for the enhancement of prostaglandin E2-, isoprenaline-or GTP-stimulated adenylyl cyclase activity, we conclude that dexamethasone treatment sensitizes cyclic AMP formation in resting human lymphocytes by altering the adenylyl cyclase catalyst rather than G-proteins or hormone receptors. This results in an enhanced capability of cyclic AMP generating agonists to inhibit early steps of lymphocyte activation.

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“…Phospholipase A, mobilizes free arachidonic acid from cellular stores, which is then metabolized by cyclooxygenases and lipoxygenases to produce prostaglandins, eicosanoids, and leukotrienes (Moncada et al, 1985). Some of the observed effects of IL-1p are actually mediated by these metabolites of arachidonic acid (Akahoshi et al, 1988;Garrett and Mundy, 1989;Goldring and Krane, 1987;Tracey et al, 1988). For example, IL-1p decreases the synthesis of type I and I11 collagens by human synoviocytes, dermal fibroblasts, and chondrocytes (Goldring and Krane, 1987).…”

Section: Discussionmentioning

confidence: 99%

Il‐1β and prostaglandins regulate integrin mRNA expression

Milam

Magnuson

Steffensen

et al. 1991

Journal Cellular Physiology

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The purpose of this study was to examine the effects of IL-1 beta on integrin expression in MG-63 human osteosarcoma cells. Human recombinant IL-1 beta (rIL-1 beta) produced significant increases in both alpha 2- and alpha 5-subunit mRNA levels, as well as a smaller increase in alpha v-subunit mRNA. In contrast, IL-1 beta decreased alpha 4-subunit mRNA levels by approximately 30% relative to untreated controls. These findings suggest that human IL-1 beta differentially regulates expression of integrins. When cultures were treated with both IL-1 beta and the cyclooxygenase inhibitor, indomethacin, the expression of alpha 2-, alpha 5-, and alpha v-subunit mRNA levels were dramatically increased relative to untreated controls; co-treatment with 0.5 mM prostaglandin E2 (PGE2) partially reversed this effect. Indomethacin alone did not affect integrin mRNA levels. Treatment with IL-1 beta or IL-1 beta + indomethacin also induced significant changes in MG-63 morphology (i.e., increased cell elongation) and increased the ability of cells to contract collagen gels. PGE2 reversed the above effects on cell morphology and gel contraction. These findings indicate that (a) IL-1 beta differentially regulates the expression of integrins and (b) that PGE2, which is induced by IL-1 beta, may provide a negative feedback loop which counteracts the stimulatory effect of IL-1 beta on integrin gene expression. It is suggested that products of inflammation may affect cell behavior by differentially regulating the expression of various integrins.

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Pharmacological inhibition of interleukin-1 activity on T cells by hydrocortisone, cyclosporine, prostaglandins, and cyclic nucleotides

Cited by 13 publications

References 35 publications

Corticosteroids inhibit the generation of lymphokine-activated killer activity in vitro

Corticosteroids inhibit the generation of lymphokine-activated killer activity in vitro

Sensitization by dexamethasone of lymphocyte cyclic AMP formation: evidence for increased function of the adenylyl cyclase catalyst

Il‐1β and prostaglandins regulate integrin mRNA expression

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