Immunomodulatory effects of RXR rexinoids: modulation of high-affinity IL-2R expression enhances susceptibility to denileukin diftitox.
Rexinoids binding to both the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families of rexinoid receptors have demonstrated clinical activity in hematologic malignancies and have been shown to mediate genes associated with both growth and differentiation. RXR rexinoids have demonstrated efficacy in the treatment of cutaneous T-cell lymphomas, but the mechanism of action is unclear. We explored the immunomodulatory effects of RAR and RXR rexinoids in human T- and B-cell leukemia cells and demonstrated that RXR rexinoids are capable of up-regulating high-affinity interleukin-2 receptor (IL-2R) expression. Exposure to 10(-6) to 10(-10) M bexarotene or Panretin for 48 hours was associated with increased expression of both the p55 and p75 subunits of the IL-2R in T-cell leukemias and p75 in B-cell leukemias. Furthermore, rexinoid exposure enhanced susceptibility of the cells to denileukin diftitox fusion toxin-targeting and -intoxicating cells expressing high-affinity IL-2R. These results suggest a rationale for combining rexinoids with IL-2R-targeted therapies in lymphoid malignancies as well as possibly in autoimmune diseases.
Gorgun
Gullu
G
Department of Hematology Oncology and Experimental Therapeutics, Tufts New England Medical Center, Boston, MA 02111, USA.
Foss
Francine
F
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects; D000077610:Bexarotene; D004167:Diphtheria Toxin / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000473:pathology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism / Q000473:pathology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000473:pathology; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects* / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D004167:Diphtheria Toxin; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; D000077556:Alitretinoin; C078456:denileukin diftitox; D014212:Tretinoin; D000077610:Bexarotene