Retinoids Synergize with Interleukin-2 to Augment IFN-gamma and Interleukin-12 Production by Human Peripheral Blood Mononuclear Cells

Abstract

We have demonstrated previously that cells from both the skin and peripheral blood from patients with cutaneous T cell lymphoma (CTCL) have elevated levels of protein and mRNA for Th2 cytokines, interleukin-4 (IL-4) and IL-5, and depressed levels of Thl cytokines, IL-2 and interferon-gamma (IFN-gamma). Furthermore, IL-12 in vitro can restore IFN-gamma production by these patients' cells to near normal levels. Because retinoids exert therapeutic activity in CTCL and are potent modulators of growth and differentiation of hematopoietic cells, we investigated the role of retinoids in modulating Thl cytokine production. Peripheral blood mononuclear cells (PBMC) from normal donors and patients with CTCL were cultured with medium, IL-2, 13-cis-retinoic acid, all-trans-retinoic acid, acetretin or etretinate alone, or IL-2 plus the retinoids for 24 h, and levels of IFN-gamma were determined using ELISA. IL-2 or retinoids alone could induce low but significant levels of IFN-gamma. However, when IL-2 was cultured with each retinoid, a synergistic augmentation of IFN-gamma levels (4-fold to 90-fold) was observed except in the case of etretinate. All-trans-retinoic acid (ATRA) was the most potent IFN-y inducer. Similar studies performed using PBMC from CTCL patients indicated the IFN-gamma augmentation occurred but in a blunted manner. The IFN-y-inducing effect of ATRA and 13-cis-retinoic acid could be abrogated by addition of anti-IL-12 antibodies, suggesting that IL-12 plays a role in the synergistic upregulation of IFN-gamma. Using an IL-12 p40-specific radioimmunoassay (RIA), we confirmed the presence of IL-12 in IL-2 plus retinoid-treated culture supernatants. Purified monocytes cultured with IL-2 plus ATRA did not secrete IL-12. Only when monocytes were cocultured with lymphocytes was there an increase in IL-12 production, suggesting the involvement of a paracrine feedback loop requiring both monocytes and lymphocytes. These data suggest that retinoids can induce Th1 cytokines from normal and CTCL PBMC and that this induction may be mediated through IL-12 production.

Impairment of STAT Activation by IL-12 in a Patient with Atypical Mycobacterial and Staphylococcal Infections

“…Furthermore, a similar, selective defect in IL-2-induced IFN-␥ production was demonstrated for patients with IL-12R␤1 mutations (18). This phenomenon probably reflects the important role that IL-12 costimulation plays in IFN-␥ induction by IL-2 (27,28) and suggests that endogenous IL-12 contributes significantly to the ability of IL-2 to induce IFN-␥ production in vitro using activated PBMC. This is further supported by our observation that a neutralizing IL-12 Ab impaired IL-2-induced IFN-␥ production in assays using activated PBMC from controls.…”

Immunopathogenesis and therapy of cutaneous T cell lymphoma

“…Using a number of different RAR-specific retinoids, including all-trans-retinoic acid and 13-cis-retinoic acid, Fox et al, demonstrated that these compounds exhibited the capacity to induce IL-12-dependent IFN-γ production (75). Moreover, synergistic production of IFN-γ occurred when low concentrations of IL-2 were added to the RAR-specific retinoids.…”

Underuse of Coronary Revascularization Procedures

“…Thus, the overall efficacy of a regimen is unlikely to reflect only the effect of the timing of the first dose, and the superior efficacy of pentasaccharide over enoxaparin is likely to be due to its selective inhibition of activated factor X, its rapid onset of action, and its long half-life, which results in a complete, 24-hour antithrombotic effect. 4,5 The reports of neuraxial hematomas referred to by Dr. Landow led to strengthened precautions for the use of anticoagulation in conjunction with epidural or spinal anesthesia. Our patients underwent randomization postoperatively and only after the removal of any epidural catheter.…”

“…Yet it is clear from other data that aggressive lipid management leads to clear benefit within six months of initiating therapy. 4,5 As compared with coronary angioplasty, aggressive lipid lowering with 80 mg of atorvastatin (bringing the ratio of total cholesterol to high-density lipoprotein cholesterol down to 2.8) decreased the rate of ischemic events by 36 percent over a period of 18 months. 4 Since no trial has compared stateof-the-art medical management (especially aggressive lipid lowering) with surgery, it is difficult to conclude that coronary revascularization is underutilized, especially for patients with chronic cardiac symptoms.…”

“…3,4 In selected patients, the addition of oral retinoids may provide further benefit. 4 However, we have observed acute allograft rejection during the use of high doses of oral retinoids, a problem that may be due to the ability of these agents to induce interferon-g production, 5 which may play a part in abrogating allograft tolerance. We advocate the use of 13-cis-retinoic acid at a dose of 10 mg every day or every other day as an adjunct to the use of topical tretinoin; adverse effects have not been observed at this dose.…”