Ức chế miễn dịch bằng Glucocorticoids: Ức chế hoạt tính của NF-κB thông qua sự tổng hợp của IκB

American Association for the Advancement of Science (AAAS) - Tập 270 Số 5234 - Trang 286-290 - 1995
Nathalie Auphan‐Anezin1, Joseph A. DiDonato1, Caridad Rosette1, Arno Helmberg1, Michael Karin1
1Department of Pharmacology, Program in Biomedical Sciences, Center for Molecular Genetics, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0636, USA.

Tóm tắt

Glucocorticoids là một trong những tác nhân chống viêm và ức chế miễn dịch mạnh mẽ nhất. Chúng ức chế quá trình tổng hợp hầu hết tất cả các cytokine đã biết và một số phân tử trên bề mặt tế bào cần thiết cho chức năng miễn dịch, nhưng cơ chế hoạt động của chúng vẫn chưa rõ ràng. Nghiên cứu này chỉ ra rằng glucocorticoids là chất ức chế mạnh mẽ hoạt động của nhân tố nhân kappa B (NF-κB) trong những nghiên cứu trên chuột và các tế bào nuôi cấy. Sự ức chế này được trung gian hóa thông qua việc tăng tổng hợp protein ức chế IκBα, vốn giữ NF-κB đã được kích hoạt trong các phức hợp không hoạt động trong tế bào chất. Vì NF-κB kích thích nhiều gen điều hòa miễn dịch để đáp ứng với các kích thích viêm, việc ức chế hoạt tính của nó có thể là một thành phần chính trong hoạt động chống viêm của glucocorticoids.

Từ khóa

#glucocorticoids #NF-κB #IκBα #cytokine #chống viêm #ức chế miễn dịch #protein ức chế #cytoplasmic complexes

Tài liệu tham khảo

10.1126/science.2838908

ALKALAY I, IN-VIVO STIMULATION OF I-KAPPA-B PHOSPHORYLATION IS NOT SUFFICIENT TO ACTIVATE NF-KAPPA-B, MOLECULAR AND CELLULAR BIOLOGY 15, 1294 (1995).

ALLERGE M.L., J IMMUNOL 146, 1184 (1991).

ARYA S.K., DEXAMETHASONE-MEDIATED INHIBITION OF HUMAN T-CELL GROWTH-FACTOR AND GAMMA-INTERFERON MESSENGER-RNA, JOURNAL OF IMMUNOLOGY 133, 273 (1984).

AUPHAN N unpublished data.

BAEUERLE P.A., THE INDUCIBLE TRANSCRIPTION ACTIVATOR NF-KAPPA-B - REGULATION BY DISTINCT PROTEIN SUBUNITS, BIOCHIMICA ET BIOPHYSICA ACTA 1072, 63 (1991).

BAEUERLE P.A., ACTIVATION OF DNA-BINDING ACTIVITY IN AN APPARENTLY CYTOPLASMIC PRECURSOR OF THE NF-KAPPA-B TRANSCRIPTION FACTOR, CELL 53, 211 (1988).

10.1126/science.3140380

BEATO M, GENE-REGULATION BY STEROID-HORMONES, CELL 56, 335 (1989).

BEG A.A., THE I-KAPPA-B PROTEINS - MULTIFUNCTIONAL REGULATORS OF REL/NF-KAPPA-B TRANSCRIPTION FACTORS, GENES & DEVELOPMENT 7, 2064 (1993).

10.1126/science.3754653

BROWN K, MUTUAL REGULATION OF THE TRANSCRIPTIONAL ACTIVATOR NF-KAPPA-B AND ITS INHIBITOR, I-KAPPA-B-ALPHA, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 90, 2532 (1993).

COCKERILL P.N., THE GRANULOCYTE MACROPHAGE COLONY-STIMULATING FACTOR INTERLEUKIN-3 LOCUS IS REGULATED BY AN INDUCIBLE CYCLOSPORINE A-SENSITIVE ENHANCER, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 90, 2466 (1993).

COHEN J.J., ANTIINFLAMMATORY STE 111, (1989).

COLLART M.A., MODULATIONS OF FUNCTIONAL-ACTIVITY IN DIFFERENTIATED MACROPHAGES ARE ACCOMPANIED BY EARLY AND TRANSIENT INCREASE OR DECREASE IN C-FOS GENE-TRANSCRIPTION, JOURNAL OF IMMUNOLOGY 139, 949 (1987).

CRESSMAN D.E., I-KAPPA-B-ALPHA CAN LOCALIZE IN THE NUCLEUS BUT SHOWS NO DIRECT TRANSACTIVATION POTENTIAL, ONCOGENE 8, 2567 (1993).

CULPEPPER J.A., REGULATION OF IL-3 EXPRESSION BY GLUCOCORTICOIDS IN CLONED MURINE LYMPHOCYTES-T, JOURNAL OF IMMUNOLOGY 135, 3191 (1985).

DEMARTIN R, CYTOKINE-INDUCIBLE EXPRESSION IN ENDOTHELIAL-CELLS OF AN I-KAPPA-B-ALPHA-LIKE GENE IS REGULATED BY NF-KAPPA-B, EMBO JOURNAL 12, 2773 (1993).

10.1126/science.8367725

10.1126/science.2119054

DIDONATO J unpublished data.

DIDONATO J unpublished data.

DIDONATO J.A., PHOSPHORYLATION OF I-KAPPA-B-ALPHA PRECEDES BUT IS NOT SUFFICIENT FOR ITS DISSOCIATION FROM NF-KAPPA-B, MOLECULAR AND CELLULAR BIOLOGY 15, 1302 (1995).

DIGNAM J.D., ACCURATE TRANSCRIPTION INITIATION BY RNA POLYMERASE-II IN A SOLUBLE EXTRACT FROM ISOLATED MAMMALIAN NUCLEI, NUCLEIC ACIDS RESEARCH 11, 1475 (1983).

DOEBERITZ M.V., GLUCOCORTICOID HORMONES REDUCE THE EXPRESSION OF MAJOR HISTOCOMPATIBILITY CLASS-I ANTIGENS ON HUMAN EPITHELIAL-CELLS, EUROPEAN JOURNAL OF IMMUNOLOGY 20, 35 (1990).

GARNER M.M., A GEL-ELECTROPHORESIS METHOD FOR QUANTIFYING THE BINDING OF PROTEINS TO SPECIFIC DNA REGIONS - APPLICATION TO COMPONENTS OF THE ESCHERICHIA-COLI LACTOSE OPERON REGULATORY SYSTEM, NUCLEIC ACIDS RESEARCH 9, 3047 (1981).

GAUGLER B, EVIDENCE FOR QUANTITATIVE AND QUALITATIVE DIFFERENCES IN FUNCTIONAL ACTIVATION OF MLS-REACTIVE T-CELL CLONES AND HYBRIDOMAS BY ANTIGEN OR TCR/CD3 ANTIBODIES, EUROPEAN JOURNAL OF IMMUNOLOGY 21, 2581 (1991).

GODOWSKI P.J., UCLA S MOL CELLULAR 95, (1989).

GONZALO J.A., GLUCOCORTICOID-MEDIATED CONTROL OF THE ACTIVATION AND CLONAL DELETION OF PERIPHERAL T-CELLS INVIVO, JOURNAL OF EXPERIMENTAL MEDICINE 177, 1239 (1993).

GRILLI M, NF-KAPPA-B AND REL - PARTICIPANTS IN A MULTIFORM TRANSCRIPTIONAL REGULATORY SYSTEM, INTERNATIONAL REVIEW OF CYTOLOGY - A SURVEY OF CELL BIOLOGY, VOL 143 143, 1 (1993).

HASKILL S, CHARACTERIZATION OF AN IMMEDIATE-EARLY GENE INDUCED IN ADHERENT MONOCYTES THAT ENCODES I-KAPPA-B-LIKE ACTIVITY, CELL 65, 1281 (1991).

HENKEL T, RAPID PROTEOLYSIS OF I-KAPPA-B-ALPHA IS NECESSARY FOR ACTIVATION OF TRANSCRIPTION FACTOR NF-KAPPA-B, NATURE 365, 182 (1993).

JONAT C, ANTITUMOR PROMOTION AND ANTIINFLAMMATION - DOWN-MODULATION OF AP-1 (FOS JUN) ACTIVITY BY GLUCOCORTICOID HORMONE, CELL 62, 1189 (1990).

KNUDSEN P.J., GLUCOCORTICOIDS INHIBIT TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL EXPRESSION OF INTERLEUKIN-1 IN U937 CELLS, JOURNAL OF IMMUNOLOGY 139, 4129 (1987).

10.1126/science.8052854

LEO O, IDENTIFICATION OF A MONOCLONAL-ANTIBODY SPECIFIC FOR A MURINE T3 POLYPEPTIDE, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 84, 1374 (1987).

MERCURIO F, P105 AND P98 PRECURSOR PROTEINS PLAY AN ACTIVE-ROLE IN NF-KAPPA-B-MEDIATED SIGNAL TRANSDUCTION, GENES & DEVELOPMENT 7, 705 (1993).

NORTHROP J.P., NEGATIVE REGULATION OF INTERLEUKIN-2 TRANSCRIPTION BY THE GLUCOCORTICOID RECEPTOR, JOURNAL OF EXPERIMENTAL MEDICINE 175, 1235 (1992).

PARILLO J.E., ANN REV PHARMACOL TO 19, 179 (1979).

PARK J.H., TRANSCRIPTIONAL REGULATION OF INTERLEUKIN-3 (IL3) IN PRIMARY HUMAN T-LYMPHOCYTES - ROLE OF AP-1-BINDING AND OCTAMER-BINDING PROTEINS IN CONTROL OF IL3 GENE-EXPRESSION, JOURNAL OF BIOLOGICAL CHEMISTRY 268, 6299 (1993).

PFAHL M, NUCLEAR RECEPTOR/AP-1 INTERACTION, ENDOCRINE REVIEWS 14, 651 (1993).

RAY A, PHYSICAL ASSOCIATION AND FUNCTIONAL ANTAGONISM BETWEEN THE P65 SUBUNIT OF TRANSCRIPTION FACTOR NF-KAPPA-B AND THE GLUCOCORTICOID RECEPTOR, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 91, 752 (1994).

ROSETTE C unpublished data.

SCHEINMAN R.I., CHARACTERIZATION OF MECHANISMS INVOLVED IN TRANSREPRESSION OF NF-KAPPA-B BY ACTIVATED GLUCOCORTICOID RECEPTORS, MOLECULAR AND CELLULAR BIOLOGY 15, 943 (1995).

10.1126/science.270.5234.283

SERFLING E, UBIQUITOUS AND LYMPHOCYTE-SPECIFIC FACTORS ARE INVOLVED IN THE INDUCTION OF THE MOUSE INTERLEUKIN-2 GENE IN LYMPHOCYTES-T, EMBO JOURNAL 8, 465 (1989).

STEIN B, CROSS-COUPLING OF THE NF-THETA-B P65 AND FOS JUN TRANSCRIPTION FACTORS PRODUCES POTENTIATED BIOLOGICAL FUNCTION, EMBO JOURNAL 12, 3879 (1993).

10.1126/science.8096091

THOMPSON J.E., I-KAPPA-B-BETA REGULATES THE PERSISTENT RESPONSE IN A BIPHASIC ACTIVATION OF NF-KAPPA-B, CELL 80, 573 (1995).

TRAENCKNER EBM, A PROTEASOME INHIBITOR PREVENTS ACTIVATION OF NF-KAPPA-B AND STABILIZES A NEWLY PHOSPHORYLATED FORM OF I-KAPPA-B-ALPHA THAT IS STILL BOUND TO NF-KAPPA-B, EMBO JOURNAL 13, 5433 (1994).

ULLMAN K.S., TRANSMISSION OF SIGNALS FROM THE LYMPHOCYTE-T ANTIGEN RECEPTOR TO THE GENES RESPONSIBLE FOR CELL-PROLIFERATION AND IMMUNE FUNCTION - THE MISSING LINK, ANNUAL REVIEW OF IMMUNOLOGY 8, 421 (1990).

VACCA A, TUMOR-PROMOTING PHORBOL ESTER AND RAS ONCOGENE EXPRESSION INHIBIT THE GLUCOCORTICOID-DEPENDENT TRANSCRIPTION FROM THE MOUSE MAMMARY-TUMOR VIRUS LONG TERMINAL REPEAT, MOLECULAR ENDOCRINOLOGY 3, 1659 (1989).

WANG Y, SEX-HORMONES AND DEXAMETHASONE MODULATE INTERLEUKIN-5 GENE-EXPRESSION IN T-LYMPHOCYTES, JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY 44, 203 (1993).

WYLLIE A.H., GLUCOCORTICOID-INDUCED THYMOCYTE APOPTOSIS IS ASSOCIATED WITH ENDOGENOUS ENDONUCLEASE ACTIVATION, NATURE 284, 555 (1980).

YANGYEN H.F., TRANSCRIPTIONAL INTERFERENCE BETWEEN C-JUN AND THE GLUCOCORTICOID RECEPTOR - MUTUAL INHIBITION OF DNA-BINDING DUE TO DIRECT PROTEIN PROTEIN-INTERACTION, CELL 62, 1205 (1990).

ZABEL U, PURIFIED HUMAN I-KAPPA-B CAN RAPIDLY DISSOCIATE THE COMPLEX OF THE NF-KAPPA-B TRANSCRIPTION FACTOR WITH ITS COGNATE DNA, CELL 61, 255 (1990).

ZABEL U, NUCLEAR UPTAKE CONTROL OF NF-KAPPA-B BY MAD-3, AN I-KAPPA-B PROTEIN PRESENT IN THE NUCLEUS, EMBO JOURNAL 12, 201 (1993).

ZANKER B, EVIDENCE THAT GLUCOCORTICOSTEROIDS BLOCK EXPRESSION OF THE HUMAN INTERLEUKIN-6 GENE BY ACCESSORY CELLS, TRANSPLANTATION 49, 183 (1990).