The Cytokine Factsbook and Webfacts

By Katherine A. Fitzgerald, Luke A.J. O'Neill, Andy J.H. Gearing and Robin E. Callard

Completely revised and expanded, this second edition of The Cytokine FactsBook is the most up-to-date reference manual available for all current well-characterized interleukins, cytokines, and their receptors. An additional 52 cytokines are included, doubling the number of entries from the previous edition. The key properties of each cytokine are described and presented in a very accessible format with diagrams for each of the receptors.

The Cytokine FactsBook includes free online access to the regularly updated Cytokine Webfacts. Cytokine Webfacts is a web-based comprehensive compendium of facts about cytokines and their receptors that includes a variety of data representations, such as text, signal pathway diagrams and 3D images. This exciting resource is integrated into other databases via hypertext links to provide a unique network, and contains a web-enabled version of RasMol for viewing structures.

• Language: English
• Publisher: Academic Press
• Release date: Sep 3, 2001
• ISBN: 9780080530208

Book preview

THE CYTOKINE

FactsBook

Second Edition

Katherine A. Fitzgerald

Department of Biochemistry & Biotechnology Institute, Trinity College, Dublin, Ireland

Luke A.J. O’Neill

Department of Biochemistry & Biotechnology Institute, Trinity College, Dublin, Ireland

Andy J.H. Gearing

Biocomm International, Melbourne, Australia

Robin E. Callard

Institute of Child Health, University College London, London, UK

Table of Contents

Cover image

Title page

Other books in the FactsBook Series

Copyright

Preface

Abbreviations

Inside Front Cover

Section I: THE INTRODUCTORY CHAPTERS

Chapter 1: Introduction

AIMS OF THE BOOK

WHAT IS A CYTOKINE?

CYTOKINE FAMILIES

Chapter 2: Organization of the data

THE MOLECULE

THE RECEPTORS

Chapter 3: The cytokine network

INTERACTIONS BETWEEN CYTOKINES

REGULATION OF CYTOKINE PRODUCTION AND ACTION

Chapter 4: Cytokine Receptor Superfamilies

INTRODUCTION

THE HAEMATOPOIETIC RECEPTOR SUPERFAMILY

THE INTERFERON RECEPTOR SUPERFAMILY

THE TNF RECEPTOR SUPERFAMILY

IL-1/TOLL-LIKE RECEPTORS

THE PROTEIN TYROSINE KINASE RECEPTOR SUPERFAMILY

CHEMOKINE RECEPTOR SUPERFAMILY

Section II: THE CYTOKINES AND THEIR RECEPTORS

Interleukins

IL-1

THE MOLECULES

THE IL-1 RECEPTORS

IL-2

THE MOLECULE

THE IL-2 RECEPTOR

IL-3

THE MOLECULE

THE IL-3 RECEPTOR

IL-4

THE MOLECULE

THE IL-4 RECEPTOR

IL-5

THE MOLECULE

THE IL-5 RECEPTOR

IL-6

THE MOLECULE

THE IL-6 RECEPTOR

IL-7

THE MOLECULE

THE IL-7 RECEPTOR

IL-8

THE MOLECULE

THE IL-8 RECEPTORS (CXCR1 and CXCR2)

IL-9

THE MOLECULE

THE IL-9 RECEPTOR

IL-10

THE MOLECULE

THE IL-10 RECEPTOR

IL-11

THE MOLECULE

THE IL-11 RECEPTOR

IL-12

THE MOLECULE

THE IL-12 RECEPTOR

IL-13

THE MOLECULE

THE IL-13 RECEPTOR

IL-14

THE MOLECULE

THE IL-14 RECEPTOR

IL-15

THE MOLECULE

THE IL-15 RECEPTOR

IL-16

THE MOLECULE

THE IL-16 RECEPTOR

IL-17

THE MOLECULE

THE IL-17 RECEPTOR

IL-18

THE MOLECULE

THE IL-18 RECEPTOR

Other cytokines and chemokines (in alphabetical order)

Activin

THE MOLECULE

THE ACTIVIN RECEPTOR

Amphiregulin

THE MOLECULE

THE AMPHIREGULIN RECEPTOR

Angiostatin

THE MOLECULE

THE ANGIOSTATIN RECEPTOR

Apo2L

THE MOLECULE

THE Apo2L/TRAIL RECEPTOR

APRIL

THE MOLECULE

THE APRIL RECEPTOR

BAFF

THE MOLECULE

THE BAFF RECEPTOR

4-1BBL

THE MOLECULE

THE 4-1BBL RECEPTOR

BCA-1

THE MOLECULE

THE BCA-1 RECEPTOR, CXCR5

BDNF

THE MOLECULE

THE BDNF RECEPTORS

Betacellulin

THE MOLECULE

THE BETACELLULIN RECEPTOR

BMPs

THE MOLECULE

THE BMP RECEPTOR

CD27L

THE MOLECULE

THE CD27L RECEPTOR

CD30L

THE MOLECULE

THE CD30L RECEPTOR CD30

CD40L

THE MOLECULE

THE CD40L RECEPTOR CD40

6Ckine

THE MOLECULE

THE RECEPTORS, CCR7 and CXCR3

CNTF

THE MOLECULE

THE CNTF RECEPTOR

CT-1

THE MOLECULE

THE CT-1 RECEPTOR

CTACK

THE MOLECULE

THE RECEPTOR, CCR10

EGF

THE MOLECULE

THE EGF RECEPTOR

ELC

THE MOLECULE

THE ELC RECEPTOR, CCR7

ENA-78

THE MOLECULE

THE ENA-78 RECEPTOR, CXCR2

Eotaxin 1

THE MOLECULE

THE RECEPTOR, CCR3

Eotaxin 2

THE MOLECULE

THE RECEPTOR, CCR3

Eotaxin 3

THE MOLECULE

Amino acid sequence for human eotaxin 3

THE RECEPTOR, CCR3

Epo

THE MOLECULE

THE EPO RECEPTOR

FasL

THE MOLECULE

THE FASL RECEPTOR, FAS/APO1

FGF

THE MOLECULES

THE FGF FAMILY

THE FGF RECEPTORS

Flt3 L

THE MOLECULE

THE FLT3 LIGAND RECEPTOR FLT3/FLK2 (CD135)

Fractalkine

THE MOLECULE

THE FRACTALKINE RECEPTOR, CX3R1

GCP-2

THE MOLECULE

THE GCP-2 RECEPTORS, CXCR1 and CXCR2

G-CSF

THE MOLECULE

THE G-CSF RECEPTOR

GDNF

THE MOLECULE

THE GDNF RECEPTOR

GITRL

THE MOLECULE

THE GITRL RECEPTOR

GM-CSF

THE MOLECULE

THE GM-CSF RECEPTOR

GROα, β and γ

THE MOLECULES

THE GRO FAMILY RECEPTOR, CXCR2

Growth hormone

THE MOLECULE

THE GH RECEPTOR

HB-EGF

THE MOLECULE

THE HB-EGF RECEPTOR

HCC-1

THE MOLECULE

THE HCC-1 RECEPTOR, CCR1

HCC-4

THE MOLECULE

THE HCC-4 RECEPTORS

HGF

THE MOLECULE

THE HGF RECEPTOR

I-309/TCA-3

THE MOLECULES

THE I-309/TCA-3 RECEPTOR, CCR8

IGF I and II

THE MOLECULES

THE IGF RECEPTORS

IFNα and IFNω

THE MOLECULES

THE IFNα RECEPTORS

IFNβ

THE MOLECULE

THE IFNβ RECEPTOR

IFNγ

THE MOLECULE

THE IFNγ RECEPTOR

γIP-10

THE MOLECULE

THE RECEPTOR, CXCR3

ISG-15

THE MOLECULE

THE ISG-15 RECEPTOR

I-TAC

THE MOLECULE

THE RECEPTOR, CXCR3

LARC

THE MOLECULE

THE RECEPTOR, CCR6

Leptin

THE MOLECULE

THE LEPTIN RECEPTOR

LIF

THE MOLECULE

THE LIF RECEPTOR

LIGHT

THE MOLECULE

THE LIGHT RECEPTORS, HVEM, LTβR and DcR3

Lptn

THE MOLECULE

THE Lptn RECEPTOR, XCR1

LT (TNFβ)

THE MOLECULE

THE LT RECEPTORS

MCP-1, -2, -3, -4 and -5

THE MOLECULES

THE MCP RECEPTORS, CCR1, CCR2, CCR3, CCR5, CCR11

M-CSF

THE MOLECULE

THE M-CSF RECEPTOR

MDC

THE MOLECULE

THE RECEPTOR, CCR4

MEC

THE MOLECULE

THE MEC RECEPTORS, CCR3 and CCR10

MIF

THE MOLECULE

THE MIF RECEPTORS

MIG

THE MOLECULE

THE MIG RECEPTOR, CXCR3

MIP-1α

THE MOLECULE

THE MIP-1α RECEPTORs, CCR1 AND CCR5

MIP-1β

THE MOLECULE

THE MIP-1β RECEPTOR, CCR5

MSP

THE MOLECULE

THE MSP RECEPTOR (RON)

NGF

THE MOLECULE

THE NGF RECEPTORS

NT-3

THE MOLECULE

THE NT-3 RECEPTORS

NT-4

THE MOLECULE

THE NT-4 RECEPTORS

OSM

THE MOLECULE

Physicochemical properties of OSM

THE OSM RECEPTOR

OX-40L

THE MOLECULE

THE OX-40L RECEPTOR

PBP, CTAP-III, NAP-2 and βTG

THE MOLECULES

THE RECEPTOR CXCR1 and CXCR2

PDGF

THE MOLECULES

THE PDGF RECEPTORS

PF-4

THE MOLECULES

THE PF-4 RECEPTOR

Prolactin

THE MOLECULE

THE PRL RECEPTORS

RANTES

THE MOLECULE

THE RANTES RECEPTORS CCRl, CCR3, CCR5 and CCR9

SCF

THE MOLECULE

THE SCF RECEPTOR

SDF-1

THE MOLECULE

THE SDF-1 RECEPTOR, CXCR4

TARC

THE MOLECULE

THE RECEPTORS, CCR4 and CCR8

TECK

THE MOLECULE

THE TECK RECEPTOR, CCR9

TGFα

THE MOLECULE

THE TGFα RECEPTOR

TGFβ1

THE MOLECULE

THE TGFβ RECEPTORS

TNFα

THE MOLECULE

THE TNF RECEPTORS

Tpo

THE MOLECULE

THE THROMBOPOIETIN RECEPTOR (c-mpl)

TRANCE

THE MOLECULE

THE TRANCE RECEPTOR, RANK

TSLP

THE MOLECULE

THE TSLP RECEPTOR

Physicochemical properties of the TLSP receptor

TWEAK

THE MOLECULE

THE TWEAK RECEPTOR

VEGF

THE MOLECULE

THE VEGF RECEPTORS

Appendix I: Cytokine standards

Appendix II: WWW Sites for DNA and Protein Databases

Appendix III: Internet Resources for Transgenic and Targeted Mutation Research

Index

Other books in the FactsBook Series

Robin Callard and Andy Gearing

The Cytokine FactsBook

Steve Watson and Steve Arkinstall

The G-Protein Linked Receptor FactsBook

Shirley Ayad, Ray-Boot Handford, Martin J. Humphries, Karl E. Adler and

C. Adrian Shuttleworth

The Extracellular Matrix FactsBook, 2nd edn

Grahame Hardie and Steven Hanks

The Protein Kinase FactsBook

The Protein Kinase FactsBook CD-Rom

Edward C. Conley

The Ion Channel FactsBook

I: Extracellular Ligand-Gated Channels

Edward C. Conley

The Ion Channel FactsBook

II: Intracellular Ligand-Gated Channels

Edward C. Conley and William J. Brammar

The Ion Channel FactsBook

IV: Voltage-Gated Channels

Kris Vaddi, Margaret Keller and Robert Newton

The Chemokine FactsBook

Marion E. Reid and CHristine Lomas-Francis

The Blood Group Antigen FactsBook

A. Neil Barclay, Marion H. Brown, S.K. Alex Law, Andrew J. McKnight, Michael G. Tomlinson and P. Anton van der Merwe

The Leucocyte Antigen FactsBook, 2nd edn

Robin Hesketh

The Oncogene and Tumour Suppressor Gene FactsBook, 2nd edn

Jeffrey K. Griffith and Clare E. Sansom

The Transporter FactsBook

Tak W. Mak, Josef Penninger, John Rader, Janet Rossant and Mary Saunders

The Gene Knockout FactsBook

Bernard J. Morley and Mark J. Walport

The Complement FactsBook

Steven G.E. Marsh, Peter Parham and Linda Barber

The HLA FactsBook

Hans G. Drexler

The Leukemia-Lymphoma Cell Line FactsBook

Clare M. Isacke and Michael A. Horton

The Adhesion Molecule FactsBook, 2nd edn

Marie-Paule Lefranc and Gérard Lefranc

The Immunoglobulin FactsBook

Marie-Paule Lefranc and Gérard Lefranc

The T Cell Receptor FactsBook

Vincent Laudet and Hinrich Gronemeyer

The Nuclear Receptor FactsBook

Copyright

This book is printed on acid-free paper.

Copyright © 2001 by ACADEMIC PRESS

All Rights Reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher.

Academic Press

A Harcourt Science and Technology Company

Harcourt Place, 32 Jamestown Road, London NW1 7BY, UK

http://www.academicpress.com

Academic Press

A Harcourt Science and Technology Company

525 B Street, Suite 1900, San Diego, California 92101-4495, USA

http://www.academicpress.com

ISBN 0-12-155142-3

Library of Congress Catalog Number: 2001092474

A catalogue record for this book is available from the British Library

INSTRUCTIONS ON GAINING ACCESS TO THE ON-LINE VERSION OF THE CYTOKINE FACTSBOOK, SECOND EDITION

Access for a limited period to an on-line version of The Cytokine FactsBook, Second Edition is included in the purchase price of the print edition.

The on-line version has been uniquely and persistently identified by the Digital Object Identifier (DOI)

doi: 10.1006/bkcf.2001

By following the link

http://dx.doi.org 10.1006 bkcf.2001

from any Web Browser, buyers of the Cytokine FactsBook, Second edition will find instructions on how to register for access.

If you have any problems with accessing the on-line version, e-mail [e-mail]

Typeset by Bibliocraft, Dundee, Scotland

Printed and bound in Great Britain by Bookcraft, Bath, Somerset.

01 02 03 04 05 06 07 BC 9 8 7 6 5 4 3 2 1

Preface

The updating of the Cytokine FactsBook was started by Robin Callard in 1998. Given the rate at which new cytokines were being discovered and characterized, the work was then shared out, with Kate Fitzgerald. Luke O’Neill and Andy Gearing contributing. Kate Fitzgerald in particular did much of the work on novel cytokines. There are many people who have helped with advice and information during the writing of this book. In particular, we would like to mention Ewan Robson (Dept. of Pathology, University of Cambridge) and Eleanor Dunn (Trinity College Dublin) for help with database searches and structural models respectively. We also wish to thank Tessa Picknett. Margaret MacDonald and Emma Parkinson for their patience and hard work in getting the manuscript into press.

R.E.C. also wishes to acknowledge funding from Action Research, the Leukaemia Research Fund, the Medical Research Council, and the Wellcome Trust.

A.J.H.G. wishes to thank Kate Owen for cheery help, British Biotech for employment, Academic Press for very nearly understanding I had a day job (sorry Tessa!) and finally Frances, Jamie and Catherine.

K.F. wishes to acknowledge funding from Enterprise Ireland and the European Union and members (both past and present) of the Inflammation Group. Trinity College Dublin (in particular Ewan Robson and Eleanor Dunne) for much appreciated help.

L.O.N. wishes to acknowledge funding from the Health Research Board. Enterprise Ireland, Bioresearch Ireland, the European Union and finally Margaret. Stevie and Sam.

There will undoubtedly be some omissions and errors in this volume although we hope they will be infrequent. We would greatly appreciate being informed of any inaccuracies by writing to the Editor, Cytokine FactsBook, Academic Press. Harcourt Place, 32 Jamestown Road, London, NW1 7BY, UK, so that these can be rectified in future editions.

Katherine Fitzgerald

Andy Gearing

Luke O’Neill

Robin Callard

Abbreviations

CSF Colony-stimulating factor

DAG 1,2-Diacylglycerol

EBV Epstein–Barr virus

FADD Fas-associated death domain

FNIII Fibronectin type III domain

GAG Glycosaminoglycan

GAP GTPase-activating protein

GF Growth factor

GPI Glycosyl-phosphatidylinositol

IFN Interferon

Ig Immunoglobulin

IL Interleukin

IP3 Inositol 1,4,5-trisphosphate

IRAK IL-1 receptor associated kinase

JAK Janus kinase

LAK Lymphokine-activated killer

LPS Lipopolysaccharide

LRR Leucine-rich region

LTR Long terminal repeat

Mr Molecular ratio

NK Natural killer

ORF Open reading frame

PGE2 Prostaglandin E2

PHA Phytohaemagglutinin

PI Phosphatidylinositol

PIP2 Phosphatidylinositol bisphosphate

PKC Protein kinase C

PLC Phospholipase C

PLD Phospholipase D

PTK Protein tyrosine kinase

SCID Severe combined immunodeficiency

STAT Signal transducer of activated transcription

TCR T-cell receptor

TIR Toll/IL-1 receptor

TLR Toll-like receptor

TRADD TNF receptor-associated death domain

TRAF TNF receptor-associated factor

4PS IL-4 induced phosphotyrosine substrate

Abbreviations for all the cytokines are not included here as the abbreviation and full name appears at the beginning of each entry.

Inside Front Cover

‘Now what I want is, Facts. Teach these boys and girls nothing but Facts. Facts alone are wanted in life. Plant nothing else, and root out everything else. You can only form the minds of reasoning animals upon Facts: nothing else will ever be of any service to them.’

From Hard Times, by Charles Dickens

Section I

THE INTRODUCTORY CHAPTERS

1

Introduction

AIMS OF THE BOOK

The main aim of this book is to provide a compendium of human and murine cytokines and their receptors. It is an updated version of the original Cytokine FactsBook published in 1994. The number of cytokines covered in the 1994 edition was 50. This version provides an update on these cytokines and an additional 51 cytokines are covered. The information provided is confined largely to physicochemical properties and includes amino acid sequences. The biological properties are not treated in detail but are described briefly, as are the major signal transduction pathways activated by each cytokine. There are also introductory chapters on the nature of cytokines and cytokine families, the cytokine network, cytokine receptor superfamilies and chemokines.

WHAT IS A CYTOKINE?

Cytokines are soluble proteins or glycoproteins produced by leukocytes, and in many cases other cell types, which act as chemical communicators between cells, but not as effector molecules in their own right. They have many roles, but a unifying feature of most cytokines is that they are regulators of host defence against pathogens and/or the inflammatory response. Most are secreted, but some can be expressed on the cell membrane, and others are held in reservoirs in the extracellular matrix. Cytokines bind to specific receptors on the surface of target cells that are coupled to intracellular signal transduction and second messenger pathways. Most cytokines are growth and/or differentiation factors and they generally act on cells within the haematopoietic system. There are four key features displayed by most cytokines:

1. Pleiotropy – Most cytokines have more than one action, for example IL-6 will provoke hepatocytes to produce acute phase proteins and it is also a growth factor for B cells.

2. Redundancy – Most cytokines have biological effects also observed in another cytokine, for example both IL-2 and IL-15 promote T cell proliferation.

3. Potency – Most cytokines act in the nanomolar to femtomolar range.

4. Action as part of a network or cascade – Most cytokines are part of a cascade of cytokines released in succession, often act in synergy, and are often counter-regulated by inhibitory cytokines or soluble receptors.

Most of these features can be explained in terms of receptors and signal transduction. Cytokines are pleiotropic because their receptors are expressed on multiple cell types and the signalling pathways activated will increase gene expression specific for that cell type. Similarities in the predicted amino acid sequences within the cytosolic domain of cytokine receptors lead to similar signals being generated by different cytokines, hence the redundancy. Cytokines are potent because of the very high affinity which cytokine receptors have for their ligands: most cytokine receptors have a negligible ‘off’ rate.

The number of proteins which may be classified as cytokines will become apparent when the full human genome sequence is annotated. At this stage it is possible to predict the number of homologues for certain cytokines – for example there are at least 15 proteins that are similar in sequence to TNF, while at least five proteins encode homologues of IL-1. Cytokines are likely to account for a significant percentage of the thousands of secreted proteins made by cells. Attempts to annotate and describe the precise function of all cytokines represents a huge challenge but will be necessary for a full understanding of how the immune system in particular functions in health and disease.

Most of the molecules covered in this book fall easily within these definitions of cytokines, but some do not. Erythropoietin (Epo) is not produced by leukocytes, but does act on haematopoietic precursors to generate red blood cells, and its receptor belongs to the type I (haematopoietin) receptor superfamily. Nerve growth factor (NGF), neurotrophin-3 (NT-3), and brain-derived neurotrophic factor (BDNF) are all members of the same family of cytokines, which are produced and act predominantly in the nervous system, but NGF also affects B cells, and its low-affinity receptor is related to the tumour necrosis factor receptor (TNFR). Not all soluble peptide mediators are considered to be cytokines (e.g. insulin) and these exceptions have not been included. In the end, the decision whether to include a molecule as a cytokine or not must be somewhat arbitrary. If there are any omissions which offend, please let the Editor know and we will try to include them in the next edition. Information in this book is provided only for human and murine (or in some cases rat) cytokines that have been cloned, and for which there is a reasonable body of biological information. Where the receptors have been cloned, they are also included.

CYTOKINE FAMILIES

It should become clear from reading the entries in this book that cytokine nomenclature owes little to any systematic relationships between molecules. This is a reflection of the different historical approaches to naming new cytokines which were based either on cell of origin or initial defining bioassay. These systems have created anomalies such as tumour necrosis factor, originally defined as causing necrosis of solid tumours, but which is now thought to be primarily an immunomodulatory and proinflammatory cytokine, and which has proven ineffective as an anticancer agent in several clinical trials. The interleukin nomenclature, which merely assigns a sequential number to new factors, is a rational system, but it has not been universally applied to new factors. A consensus on the grouping of cytokines into families has settled on classifying cytokines based on the structure of their receptors¹. One somewhat surprising finding has been that although there are many cytokines, receptors for these cytokines fall into a relatively small number of families, with highly conserved structural features¹–⁶. As stated above, this provides an explanation for the redundancy in biological effects among cytokines, with many different cytokines affecting T-cell function for example. Redundancy can now be explained in terms of similar signal transduction pathways being triggered by highly similar receptors.

There are six major families of cytokine receptors (each family being defined by similar sequences in their cytosolic domains) and most of the cytokines with known receptors described in this book fall into one of the six families (Table 1). Within each family there are homologies in receptor sequence both intracellularly and extracellularly but there are also differences, particularly extracellularly where additional domains can be found. These subtleties are discussed in more detail in Chapter 4. Broadly speaking, the functions of cytokines fitting into each family are also conserved and these are also listed in Table 1. Because cytokines are so pleiotropic, however, it is difficult to classify them according to function. Because the receptors show homologies extracellularly, the structures of the cytokines themselves are also conserved, with subtle differences allowing cytokines to discriminate between receptors. The structural features of cytokines are therefore also listed in Table 1 and solid models of representatives of each of the families, some as a complex with their receptor, are shown in Figure 1.

Table 1.1

Cytokine families grouped according to receptor structure

Figure 1.1 Crystal structures of cytokines and cytokine/receptor complexes. All structures are depicted in ribbon format. Coordinates were downloaded from the Protein Data Bank and viewed using the Swiss-PDB Viewer v3.51. (a) Granulocyte colony-stimulating factor with receptor (PDB I.D. 1CD9). (b) Interferon y with receptor (PDB I.D. 1FYH). (c) TNF: individual monomers (PDB I.D. 2TNF). (d) Interleukin-1β with Type I IL-1 receptor (PDB I.D. 1ITB). (e) Basic fibroblast growth factor (PDB I.D. IBFF). (f) IL-8 (PDB I.D. 3IL-8).

Receptors for three cytokines which do not fit into these families have been left out. The TGFβ receptor has a serine/threonine kinase domain and is the only cell activator to have a receptor with such a domain so far described. The α-chains of the receptor complexes for IL-2 and IL-15 contain complement control protein domains involved in ligand binding.

Overall, it seems unlikely that cytokine nomenclature will reflect the family relationships described here, either in terms of receptor families or structures of cytokines. General principles on the functioning of cytokines within families have emerged, however, and provide a framework from which to approach the complexities inherent in the study of cytokine function.

References

1. Taniguchi, T. Science. 1995;268:251–255.

2. Stroud, R.M., et al. The Cytokine Reference. London: Academic Press, 2000;21–34.

3. Bazan, J.F. Proc. Natl Acad. Sci. USA. 1990;87:6934–6938.

4. Ihle, J.N., et al. Annu. Rev. Immunol. 1995;13:369–398.

5. Aggarwal, B.B., et al. The Cytokine Reference. New York: Academic Press, 2000;1619–1631.

6. O’Neill, L.A.J., Dinarello, C.A. Immunol. Today. 2000;21:206–209.

2

Organization of the data

Cytokine entries include the following information:

Other names

Most cytokines have more than one name. This section lists names which appear in the literature and can be directly related to the protein under discussion. We have used the interleukin nomenclature whenever this has been assigned unequivocally. All other cytokines are entered under their most commonly accepted name. Alternative names are also listed.

THE MOLECULE

At the beginning of each entry is a brief description of the molecule and its main biological properties.

Crossreactivity

The degree of amino acid sequence homology between human and mouse cytokines is given when known, together with cross-species reactivity. In some cases, comparisons with other species are also given.

Sources

A list of cell types known to produce each cytokine is included.

Bioassays

Bioassays for each cytokine are described in brief. For the most part, these have been taken from methods used by the National Institute for Biological Standards, South Mimms, UK as described in refs 1 and 2.

Physicochemical properties of the cytokines

This table includes basic physicochemical information on human and mouse cytokines. The number of amino acids and predicted molecular weight for the mature proteins are calculated after removal of the signal peptide and propeptides where relevant. In some cases the cleavage point of the signal peptide has been determined by sequencing and in others from computer prediction. In cases where the position of the signal peptide is unclear, the predicted molecular weight for the unprocessed precursor is given. Potential N-linked glycosylation sites are identified by the consensus sequence AsnXSer/Thr except when X is Pro or for the sequence AsnXSer/ThrPro which is not usually glycosylated. The number of potential sites in the table is for the extracellular portion of the molecule only.

3-D structure

Information on the tertiary structure of each cytokine is taken from the SwissProt database, original papers or from Macromolecular Structures 1991 1993 published by Current Biology³. It includes data derived from X-ray or NMR structures, or predictions based on molecular models. In some cases because of the high degree of homology in amino acid sequence, the structures are predicted to resemble that of previously solved ones.

Gene structure and chromosomal localization

The chromosomal localization for the human cytokines is taken from original papers and/or the Human Gene Mapping (HGM 11)⁴. Mouse mapping data are taken from ref. 5 or original papers in some cases. The gene structure is taken from original papers with the number of exons and introns indicated where known.

Amino acid sequences

Human and mouse amino acid sequences are given for each cytokine and receptor where known. In some cases, the murine sequence is not available and the rat sequence is given instead. The sequences for most entries were taken directly from the SwissProt Protein Sequence Database, which is a database of protein sequences produced collaboratively by Amos Bairoch (University of Geneva) and the EMBL Data Library. The data in SwissProt are derived from translations of DNA sequences from the EMBL Nucleotide Sequence Database, adapted from the Protein Identification Resource (PIR) collection, extracted from the literature or directly submitted by researchers. SwissProt contains high-quality annotation, is nonredundant and is cross-referenced to several other databases, notably the EMBL, PROSITE pattern database and PDB. In cases where a SwissProt entry does not exist for a given protein, a TrEMBL entry is given. TrEMBL is a protein sequence database supplementing the SwissProt Data Bank. TrEMBL contains the translations of all coding sequences (CDS) present in the EMBL database that are not yet integrated in SwissProt. TrEMBL can be considered as a preliminary section of SwissProt. In certain cases, cDNA nucleic acid sequences were obtained from EMBL and/or Genbank and translated using the translation tool from the Expasy Molecular Biology Server (http://www.expasy.ch/tools/#translate).

In all cases, the accession number is listed with the sequence. In all sequences, the single-letter amino acid code is used (Table 1). The numbering starts with the N-terminal amino acid after removal of the signal peptide. If the N-terminus has not been unequivocally assigned, the signal sequence is predicted according to consensus rules⁶ and numbered to –1. Propeptides removed during post-translational modifications are shown in italics. The transmembrane portions of the sequences for cytokine receptors and cytokine precursor proteins (in cases where the precursor is a transmembrane protein) are underlined. Potential N-linked glycosylation sites marked by N in bold type are predicted by the presence of sequences AsnXSer or AsnXThr with the exceptions AsnProSer/Thr which are not normally glycosylated and AsnXSer/ThrPro which are often not glycosylated⁷–⁹. O-Linked glycosylation occurs at Ser or Thr residues. Although there is no clear-cut sequence motif that invariably indicates O-linked glycosylation, it usually occurs where there is a preponderance of Ser, Thr and Pro. Sequence motifs of particular interest are annotated under the sequence.

Table 1

Single-letter amino acid codes

THE RECEPTORS

A brief description of the cytokine receptors with comments on important features is given in this section. The criteria used for defining cytokine receptor superfamilies are given in Chapter 4. The symbols used to represent the various domains, glycosylation and membrane attachment are given in Figure 1.

Figure 1 Models for domains and repeats found in leukocyte membrane proteins. These models are used in the diagrams drawn for the entries in Section II.

Distribution

The tissue distribution of the receptors has been determined in some cases by ligand (cytokine) binding studies. Otherwise, it is assumed from mRNA expression or biological response.

Physicochemical properties of the receptors

This table includes the number of amino acids in both the precursor and the mature processed protein, predicted and expressed molecular ratio (Mr), and the number of N-linked glycosylation sites in the extracellular portion of the mature protein. The affinity of the receptor for its cytokine is also given. These data have been taken from binding studies with the natural receptor or the cloned receptor expressed on cells transfected with receptor cDNA.

Signal transduction

This section describes in brief what is known about the intracellular signal transduction pathways coupled to the cytokine receptors.

Chromosomal location

The chromosomal location of the receptors is taken from original papers and/or HGM 11⁴,⁵.

Amino acid sequences of cytokine receptors

Sequence data for human and mouse receptors are given as described above for the cytokines. Transmembrane domains are underlined and short sequences of particular interest, such as the WSXWS motif in fibronectin type III (FNIII) domains, are annotated under the sequence.

References

1. Thorpe, R., et al. Blood Rev. 1992;6:133–148.

2. Wadhwa, M., et al. Balkwill F.R., ed. Cytokines: A Practical Approach. IRL Press: Oxford, 1992; 309–330.

3. Hendrickson W.A., Wuthrich K., eds. Macromolecular Structures. 1991, 1992. Current Biology: London, 1993.

4. Human Gene Mapping 11 (HGM 11). Cytogenet. Cell Genet. 1991;58:1–2200.

5. Copeland, N.G., et al. Science. 1993;262:57–66.

6. von Heijne, G. Eur. J. Biochem. 1983;133:17–21.

7. Bause, E., Hettkamp, H. FEBS Lett. 1979;108:341–344.

8. Kornfeld, R., Kornfeld, S. Annu. Rev. Biochem. 1985;54:631–664.

9. Gavel, Y., von Heijne, G. Protein Eng. 1990;3:433–442.

10. Barclay, N.A., et al. The Leucocyte Antigen FactsBook. Academic Press: London, 1993.

3

The cytokine network

INTERACTIONS BETWEEN CYTOKINES

Individually, cytokines are potent molecules which, in vitro, can cause changes in cell proliferation, differentiation and movement at nanomolar to picomolar concentrations. Injection of cytokines into animals and humans either systemically or locally can also have profound effects on leukocyte migration and function, haematopoietic cell numbers, temperature regulation, acute phase responses, tissue remodelling and cell survival. The individual entries in this book describe the specific properties of each cytokine, but delineation of the mechanisms by which cytokines cause these effects is complicated by the tendency of cytokines to affect the expression of other cytokines and/or their receptors. In addition, it is clear that there are no circumstances in vivo in which cytokines are produced individually. Rather they are produced together with other cytokines in