Advances in Immunology (eBook)

Frank J. Dixon (Herausgeber)

eBook Download: PDF

1997 | 1. Auflage
408 Seiten
Elsevier Science (Verlag)
978-0-08-057841-5 (ISBN)

Infos

KEY TOPICS:

Ig A Deficiency

The Role of Cellular Immunity in Protection against HIV Infection

Mouse Mammary Tumour Virus: Immunological Interplays between Virus and Host

The Transporter Associated with Antigen Processing

NF-kB in cytokine gene expression

NF-kB as a target for immunosuppressive and anti-inflammatory molecules


Key Features
* A Deficiency
* The Role of Cellular Immunity in Protection against HIV Infection
* Mouse Mammary Tumor Virus: Immunological Interplays between Virus and Host
* The Transporter Associated with Antigen Processing
* NF-kB in cytokine gene expression
* NF-kB as a target for immunosuppressive and anti-inflammatory molecules

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Ig A DeficiencyThe Role of Cellular Immunity in Protection against HIV InfectionMouse Mammary Tumour Virus: Immunological Interplays between Virus and HostThe Transporter Associated with Antigen ProcessingNF-kB in cytokine gene expressionNF-kB as a target for immunosuppressive and anti-inflammatory molecules- The Role of Cellular Immunity in Protection against HIV Infection- Mouse Mammary Tumor Virus: Immunological Interplays between Virus and Host- The Transporter Associated with Antigen Processing- NF-kB in cytokine gene expression- NF-kB as a target for immunosuppressive and anti-inflammatory molecules

Inhalt

Front Cover 1
Advances in Immunology, Volume 65 4
Copyright Page 5
Contents 6
Contributors 10
Chapter 1. NF-IL6 and NF-KB in Cytokine Gene Regulation 12
I. Introduction 12
II. NF-IL6 12
III. NF-KB 22
IV. Protein–Protein Interaction in Gene Regulation 27
V. Cytokine Gene Regulation 36
VI. Cytokine Induction in NF-IL6 Family Knockout Mice 40
VII. Cytokine Induction in NF-KB Knockout Mice 41
VIII. Conclusion 43
References 44
Chapter 2. Transporter Associated with Antigen Processing 58
I. Introduction 58
II. ABC Transporters 67
III. Gene Structure of TAP and Its Regulation 69
IV. TAP Protein Structure 72
V. TAP Polymorphism 82
VI. Function of the TAP Complex 86
VII. TAP and MHC Class I Assembly 98
VIII. TAP in Disease 103
IX. Concluding Remarks 107
References 107
Chapter 3. Contents NF-KB as a Frequent Target for Immunosuppressive and Anti-Inflammatory Molecules 122
I. Introduction 122
II. Glucocorticoids and Other Steroid Hormones 129
III. Cyclosporin A and FK506 131
IV. Rapamycin 132
V. Salicylates 132
VI. Antioxidants and Inhibitors of Enzymes Generating Reactive Oxygen Intermediates 133
VII. Anti-TNF-a Antibodies and Gold Compounds in Treatment of Rheumatoid Arthritis 134
VIII. Immunosuppressive Activity of cAMP 135
IX. The Bacterial Metabolite Spergualin 136
X. The Fungal Metabolite Gliotoxin 137
XI. Viral Strategies to Control NF-KB 138
XII. Conclusion 139
References 143
Chapter 4. Mouse Mammary Tumor Virus: Immunological Interplays between Virus and Host 150
I. Introduction 150
II. Mouse Mammary Tumor Virus 151
III. Structure of the SAg Protein 168
IV. Immune Response to MMTV 178
V. T and B Cell Response to Endogenous Mtv 207
VI. Comparison with Other SAgs 219
VII, Conclusions 222
Chapter 5. IgA Deficiency 256
I. Introduction 256
II. Clinical Manifestations of IgA Deficiency 257
III. IgA Structure, Production, and Function 259
IV. IgA Deficiency Viewed in the Context of the Genesis of IgA-Producing Cells 262
V. Relationship of IgA D with Common Variable Immunodeficiency 267
VI. Genetic Susceptibility for IgAD and CVID 267
VII. Pathogenesis of IgA Deficiency 271
VIII. Conclusions 274
References 274
Chapter 6. Role of Cellular Immunity in Protection against HIV Infection 288
I. Introduction 288
II. Cellular Immunity in the Control of Other Viruses 289
III. CTL Effector Mechanisms 291
IV. HLA and HIV Infection 295
V. The Nature of HIV-Specific CTLs 297
VI. Measurement of HIV-Specific CTLs 298
VII. Role of HIV-Specific CTLs in the Natural History of HIV Infection 301
VIII. Does HIV Escape from the CTL Response? 322
IX. Therapeutic Implications of the Importance of HIV-Specific CTLs 328
X. Conclusions 333
References 334
Chapter 7. High Endothelial Venules: Lymphocyte Traffic Control and Controlled Traffic 358
I. Introduction 358
II. Structure of High Endothelial Venules 359
III. Role of HEVs and Lymphocyte Migration 361
IV. In Vitro HEV Binding Assay 362
V. Molecules Determining HEV–Lymphocyte Interactions 363
VI. L Selectin 363
VII. Integrins and Their Role in Lymphocyte–HEV Interactions 369
VIII. CD44 and Lymphocyte Homing 370
IX. Homing Receptor Ligands on High Endothelial Cells 371
X. Additional Molecules on High Endothelial Venules Involved in Lymphocyte Migration 376
XI. Adhesion and Extravasation 376
XII . Adhesion Cascade and Specificity of Lymphocyte Homing 380
XIII. Regulation of the Unique Features of the High Endothelial Venule 383
XIV. Concluding Remarks 390
References 391
Index 408
Contents of Recent Volumes 418

Textauszug

NF-IL6 and NF-κB in Cytokine Gene Regulation*

Shizuo Akira*; Tadamitsu Kishimoto†    * Department of Biochemistry, Hyogo College of Medicine, Nishinomiya, Hyogo 663, Japan
† Osaka University Medical School, Department of Medicine III, Suita, Osaka 565, Japan

I Introduction

The immune system is regulated through a complicated network modulated by a variety of cytokines and their cognate receptors. Transcriptional activation of inflammatory response genes, such as the genes for cytokines, their receptors, cell adhesion molecules, and acute phase proteins, is regulated by a specific assembly of transcription factors on the enhancers and promoters of these genes. Accumulating evidence indicates that a relatively small number of transcription factors play a critical role in achieving the high level of orchestration required for the complex gene expression involved in the immune response. These include the NF-κB, NF-IL6, CREB/ATF, Jun–Fos, STAT, and NF-AT families of transcription factors. On the other hand, dysfunctional regulation of these transcription factors may induce immunologically mediated diseases. In this review, we highlight how protein–protein interactions between transcription factors may modulate the activation of the cytokine genes. Particular attention is directed to two important families of transcription factors, NF-IL6 and NF-κB.

II NF-IL6

A STRUCTURE AND FUNCTION OF NF-IL6

NF-IL6 was originally identified as a nuclear factor binding to a 14-bp palindromic sequence (ACATTGCACAATCT) within an IL-1 responsive element in the human IL-6 gene (Isshiki et al., 1990). Cloning the cDNA encoding human NF-IL6 revealed that it has a high degree of homology with C/EBP in the carboxy-terminal basic and leucine zipper domains, responsible for DNA binding and dimerization, respectively (Akita et al., 1990). NF-IL6 recognizes the same nucleotide sequences as C/EBP. Both proteins bind to a variety of the divergent nucleotide sequences with different affinities, and the consensus sequence is T(T/G)NNGNNAA(T/G). NF-IL6 homologs in other species have been cloned under the names AGP/EBP (Chang et al., 1990), LAP (Descombes et al., 1990), IL-6DBP (Poli et al., 1990), rNFIL-6 (Metz and Ziff, 1991), C/EBPβ (Cao et al., 1991), CRP2 (Williams et al., 1991), and NF-M (Katz et al., 1993). The NF-IL6 gene is intronless, and it produces two proteins—LAP (liver-enriched transcriptional activator protein, equivalent to NF-IL6) and LIP (liver inhibitory protein)—by the alternative use of two AUG initiation codons within the same open reading frame (Descombes and Schibler, 1991). LIP contains DNA binding and dimerization domains but is devoid of the N-terminal transcriptional activation domain and therefore behaves as an antagonist of LAP-induced transcription. The ratio of these two forms varies depending on the cell type and on the developmental stage and can be altered to activation dominance by IL-6 or other extracellular signals such as retinoic acid (Descombes and Schibler, 1991; Hsu et al., 1994).

B ACTIVATION OF NF-IL6 THROUGH PHOSPHORYLATION

NF-IL6 activity is regulated by phosphorylation. Transient expression of a series of site-directed mutants of NF-IL6 and subsequent phosphopeptide mapping identified three phosphoiylated residues: Ser-231 and Thr-235, both located within the serine-rich domain (SRD) adjoining bZIP, and Ser-325 that is located within the leucine zipper. The amino acid sequence immediately surrounding Thr-235 (SSPPGTPSP) coincides with the consensus for MAP kinase recognition. In fact, a synthetic peptide containing Thr-235 was phosphoiylated in vitro by purified MAP kinases. When vectors expressing NF-IL6 or oncogenic p21ras were cotransfected with an IL-6 promoter–luciferase gene reporter construct, simultaneous expression of both NF-IL6 and oncogenic p21ras resulted in a dramatic synergistic stimulation of the reporter gene. Two dimensional phosphopeptide mapping showed that oncogenic p21ras expression markedly augmented Thr-235 phosphorylation. Furthermore, the substitution of Ala for Thr-235 resulted in the loss of ras-dependent NF-IL6 activation. These results demonstrate that NF-IL6 is activated through phosphorylation of Thr-235 by a ras-dependent MAP kinase cascade (Nakajima et al., 1993). The molecular mechanisms of NF-IL6 transcriptional activation through phosphorylation on Thr-235 have been clarified (Kowen-Leutz et al., 1994). NF-M, the chicken homolog of NF-IL6, is a critical transcription factor required for the expression of chicken myelomonocytic growth factor (cMGF), which is distantly related to G-CSF and IL-6 (Burk et al., 1993; Katz et al., 1993). In v-myb- or v-myc-transformed cells, NF-M is the target of activated kinase oncogenes, which induce cMGF gene expression, resulting in autocrine growth stimulation. Analyses of functional domains of NF-M demonstrated that the amino-terminal domains contribute to the transactivating function of the protein, whereas the internal portion (amino acids 116–229) between bZip and the amino-terminal activating domains inhibits the transcriptional activation. A consensus sequence for MAP kinase located within the inhibitory domain is conserved between avian and mammalian NF-IL6. NF-M was activated by deleting the entire region that harbors the MAP kinase site or by a point mutation at the MAP kinase site that mimics the negative charge of a phosphate residue. These results suggest that the inhibitory regions within NF-IL6 mask the transactivation domain and prevent its interaction with the basic transcription machinery.

NF-IL6 is also phosphorylated within the leucine zipper in response to increased intracellular calcium concentrations via the activation of a calcium–calmodulin-dependent kinase (Wegner et al., 1992). In addition, the cAMP-mediated phosphorylation of NF-IL6 is associated with nuclear translocation and transcriptional activation (Metz and Ziff, 1991). NF-IL6 is activated through phosphorylation of the N-terminal domain by PKC (Trautwein et al., 1993). Thus, NF-IL6 is, in fact, activated via multiple signaling pathways (Fig. 1).

Fig. 1 Phosphoiylation of NF-IL6. P, proline rich; S, serine rich; L, leucine.

C C/EBP FAMILY MEMBERS

Following NF-IL6, several other C/EBP family members have been molecularly cloned. Currently, there are five known members of the C/EBP family (Fig. 2). These include C/EBP (Landschulz et al., 1988), NF-IL6, Ig/EBP (also referred to as GPE-1-BP and C/EBPγ) (Roman et al., 1990; Nishizawa et al., 1991), NF-IL6β (C/EBPδ) (Kinoshita et al., 1992; Kageyama et al., 1991; Cao et al., 1991; Williams et al., 1991), and CHOP-10 (gadd153) (Ron and Habener, 1992). The genes encoding these proteins map to different loci of different chromosomes; C/EBP maps to human chromosome 19q13.1 (mouse chromosome 7) (Birkenmeier et al., 1989), NF-IL6 to human chromosome 20q13.1 (mouse chromosome 2) (Hendricks-Taylor et al., 1992), NF-IL6β to human chromosome 8q11 (mouse chromosome 16) (Cleutjens et al., 1993), and CHOP-10 to human chromosome 12q13.1–q13.2 (Park et al., 1992).

Fig. 2 C/EBP family members. DNA, DNA-binding domain; P, proline rich; G, glycine rich; S, serine rich; L, leucine; E, glutamic acid; D, aspartic acid; T, threonine.

C/EBP is expressed in adipose, liver, and placental tissues that play vital roles in energy metabolism (McKnight et al., 1989). C/EBP mRNA increases markedly during the differentiation of 3 T3-L1 preadipocytes to adipocytes (Birkenmeier et al., 1989). C/EBP can transactivate the promoters of adipocyte-specific genes, a fatty acid binding protein 422 (aP2), stearoyl-CoA desaturase 1 (SCD1), and insulin-responsive glucose transporter-4 (GLUT4) (Christy et al., 1989). C/EBP is an important regulatory factor in adipocyte differentiation. Premature activation of a constitutively expressed, but inactive, C/EBP–estrogen receptor fusion protein causes premature expression of aP2 mRNA relative to die normal differentiation program (Umek et al., 1991). Other studies have also presented similar results (Lin and Lane, 1992; Freytag and Geddes, 1992). The ectopic expression of C/EBP by retroviral vectors induces adipogenesis directly in otherwise nonadipogenic NIH-3 T3 cells (Freytag et al., 1994). In contrast, antisense C/EBP RNA suppresses several adipose-specific mRNAs such as aP2, SCD1, and GLUT4, as well as triglyceride accumulation during the differentiation of 3 T3-L1 preadipocytes (Samuelsson et al., 1991; Lin and Lane, 1992).

C/EBP may also be involved in controlling the expression of genes of which the products are critical to fiver function...

Produkt-Details

• Erscheint lt. Verlag: 12.8.1997
• Sprache: englisch
• Themenwelt: Sachbuch/Ratgeber
• Themenwelt: Medizin / Pharmazie ► Allgemeines / Lexika
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Mikrobiologie / Infektologie / Reisemedizin
• Themenwelt: Studium ► Querschnittsbereiche ► Infektiologie / Immunologie
• Themenwelt: Naturwissenschaften ► Biologie ► Biochemie
• Themenwelt: Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Mikrobiologie / Immunologie
• Themenwelt: Naturwissenschaften ► Biologie ► Zellbiologie
• Themenwelt: Technik
• ISBN-10: 0-08-057841-1 / 0080578411
• ISBN-13: 978-0-08-057841-5 / 9780080578415