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Cytokine
Knockouts
Second Edition
EDITED BY

Giamila Fantuzzi
Cytokine Knockouts
 Contemporary Immunology
Cytokine Knockouts, Second Edition
Edited by Giamila Fantuzzi, 2003
Therapeutic Interventions in the Complement System
Edited by John D. Lambris and V. Michael Holers, 2000
Chemokines in Disease: Biology and Clinical Research
Edited by Caroline A. Hébert, 1999
Lupus: Molecular and Cellular Pathogenesis
Edited by Gary M. Kammer and George C. Tsokos, 1999
Autoimmune Reactions
Edited by Sudhir Paul, 1999
Molecular Biology of B-Cell and T-Cell Development
Edited by John G. Monroe and Ellen V. Rothenberg, 1998
Cytokine Knockouts
Edited by Scott K. Durum and Kathrin Muegge, 1998
Immunosuppression and Human Malignancy
Edited by David Naor, 1990
The Lymphokines
Edited by John W. Haddon, 1990
Clinical Cellular Immunology
Edited by Howard H. Weetall, 1990
 Cytokine
Knockouts
Second Edition

Edited by
Giamila Fantuzzi, PhD
University of Colorado Health Sciences Center,
Denver, CO

Foreword by

Scott K. Durum
National Cancer Institute, Frederick, MD
© 2003 Humana Press Inc.
999 Riverview Drive, Suite 208
Totowa, New Jersey 07512

www.humanapress.com

All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or
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from the Publisher.

All authored papers, comments, opinions, conclusions, or recommendations are those of the author(s), and do not
necessarily reflect the views of the publisher.

This publication is printed on acid-free paper. ∞

ANSI Z39.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Materials.

Production Editor: Tracy Catanese

Cover illustration: Fig. 2 from Chapter 7, "IL-1 Receptor Antagonist-Deficient Mice" by Martin J. H. Nicklin and
Joanna Shepherd.

Cover design by Patricia F. Cleary.

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Library of Congress Cataloging in Publication Data

Cytokine Knockouts / edited by Giamila Fantuzzi ; foreword by Scott K. Durum.--2nd ed.

p. cm. -- (Contemporary immunology)
Includes bibliographical references and index.
ISBN 1-58829-194-4 (alk. paper); 1-59259-405-0 (e-book)
1. Cytokines. 2. Gene targeting. I. Fantuzzi, Giamila. II. Series.

QR185.8.C95C9814 2002
616.07'9--dc21 2002191938
Foreword

This is the second edition of Cytokine Knockouts, an entirely new volume edited
by Giamila Fantuzzi. The first edition, edited by Kathrin Muegge and me, was inspired
by what we felt were the most important experiments in cytokinology. But at that time,
their bold messages had not yet sunk in. For example, there were papers still being
published and grants being funded studying effects of Interleukin (IL)-1 or IL-2 in the
development of thymocytes, when in fact, the knockouts of IL-1 or IL-2 had shown
no effect on the thymus (although now it looks like IL-2 does have a thymic effect—
see Chapter 9). So we thought it was useful to compile the studies on cytokine knockout
mice in a single volume.
Times have changed since the first edition of Cytokine Knockouts. These mice have
become de rigueur for immunology studies; there were a dozen papers in a recent issue
of the Journal of Immunology using knockout mice, and one paper actually used 10
different knockout lines. The second edition of Cytokine Knockouts therefore represents
far more extensive studies than the first edition with many new knockouts, emergent
phenotypic patterns, and a more precise understanding of the impact of each cytokine
knockout. Many other fields in experimental biology have been redirected by the sev-
eral thousand strains of knockout mice that have been created. How many knockouts
will there be? Possibly more than the number of genes, because multiple regions of each
gene are often deleted or replaced.
Molecular targets have been identified or eliminated based on knockout pheno-
types and most of the cytokines were shown to be benign targets. For example, tumor
necrosis factor (TNF) was hoped to be a desirable target for anti-inflammatory drugs.
The knockout of TNF or its receptors clearly predicted there should be no dire effects
from blocking TNF pharmacologically because mice completely lacking TNF from
conception showed relatively subtle abnormalities. This prediction has been vindi-
cated in the 250,000 or so patients being treated with TNF antagonists for rheumatoid
arthritis and Crohn’s disease; although it is now thought that TNF blockade awakens
latent tuberculosis infections, that is still a modest risk, and was accurately predicted
by the phenotype of knockout mice.
The technology bar has been raised. The major embryonic stem cell lines are still
from the (weird) 129 mouse strain and the basic DNA reaction has not been improved
over the extremely rare homologous recombination event. But there are new methods
for creating the targeting construct without relying on restriction sites. The practice of
simply replacing a critical gene segment with a neo cassette is now supplanted by meth-
ods for subsequently removing the troublesome neo cassette. The Cre-loxP and FLP-
FRT recombinase systems are commonly used to perform this deletion, and these systems
are also used to delete very large gene segments.
The original targeting strategy for creating knockouts deleted the gene in all tis-
sues. Clever variations have allowed study of gene function in specific cell lineages
and stages. Perhaps the first variation, Rag complementation, was used to study effects

v
vi Foreword

in the lymphocyte lineage; this was done by placing knockout ES cells into a Rag knock-
out blastocyst. For studying other hematopoietic cells, knockout fetal liver cells are
used as hematopoietic stem cells in radiation chimeras. Combining knockouts and
transgenes has allowed many strategies. For example, mice that lack a certain enzyme
have a block in thymocyte development; the enzyme is reintroduced as a transgene
restricted in expression to the thymocyte. T cells then leave the thymus, shut off
the transgene, and the effect of the enzyme is examined on subsequent T cell survival.
“Conditional knockout” has used the Cre-loxP and FLP-FRT systems to somatically
delete genes in several specific lineages, such as T cells, B cells, and macrophages.
Acute somatic deletion in specific lineages combines Cre-loxP with IFN or tetracycline
regulation—this, for example, established that antigen receptors are required for long-
term survival of lymphocytes, not just their generation.
It is disappointing that homologous recombination has not been improved to a higher
efficiency, which among other applications could make it therapeutically useful in
somatic cells in patients. For example, γc-deficient patients have been successfully treated
by retroviral gene therapy, introducing a good γc gene under a viral promoter. But most
virally introduced transgenes only function in patients for a few weeks and are then shut
off. Moreover, the risk of retroviral insertion activating oncogenes proved to be far greater
than imagined and several γc patients have developed lymphoma. A better alternative
would be to fix a bad gene (for γc, IL-7 receptor, hemoglobin, etc.) by repairing the bad
copy in a patient’s hematopoietic stem cells ex vivo, then transferring them back to the
patient. The major problem to overcome is the rare frequency of homologous recom-
bination. An even greater problem would be to repair a nonhematopoietic gene, for
example a bad collagen gene that affects tissues throughout the patient, or restoring
tumor suppressor genes that have been deleted or mutated in cancer cells. Maybe the
field needs new methods, perhaps a DNA repair enzyme, delivered with the gene of
interest that would excise the old and insert the new.
Improving the frequency of homologous recombination would also be tremendously
useful for experimental work, for example, in creating cell lines that have a specific
gene deleted or altered. Imagine a variation on Cre-lox or FLP-FRT, like the Rag pro-
teins which are extremely specific in cutting immune receptor genes and creating rear-
rangements, errors virtually never occur and efficiency is extremely high.
Knockout mice have created an expensive maintenance, storage and distribution
problem for what could become 20–100,000 different mouse strains. Jackson Labs cur-
rently handles 300 knockout strains and Taconic distributes 40. The National Cancer
Institute is cryopreserving and distributing knockout mouse strains that are relevant to
cancer research. The American Type Culture Collection, which has preserved and dis-
tributed cell lines, is now considering taking on cryopreservation and distribution of a
wide variety of mouse embryos. There is a real need for preserving these valuable strains
and, sadly, many of the less popular strains may already have been lost. Ethical concerns
have also developed, in that new knockouts and new genetic combinations can clearly
create pain and suffering in mice. It is gratifying that at least here at NIH the PI is held
responsible for anticipating and observing these problems.
When stem cell ceases to be a four letter word, future editions of this book will likely
cover knockouts in lots of other species in addition to mice. Boneless fish and chickens.
Fat-free beef. Shedless, clawless, unfinicky cats. Dogs with an aversion to garbage cans.
Foreword vii

Diurnal hamsters. Deer that eat poison ivy and avoid roadways. Thrilling revelations await
in pursuing the unnatural and undoing hundreds of millions of years of evolution.
But seriously, the second edition of Cytokine Knockouts brings together outstand-
ing world authorities on these unique mice. It is a rich resource for researchers inter-
ested in the roles cytokines play in physiological and pathological processes and in
selection of drug targets.
Scott K. Durum
National Cancer Institute
Preface

As mentioned in the preface to the first edition of Cytokine Knockouts (1998) by

the editors S. K. Durum and K. Muegge, “The technique of gene targeting or ‘knockout’
has swept through biomedical research of the 1990s as if it were the Occam’s razor of
biology. The technique provides an acid test of the function of a gene.” In the years since
the first edition of Cytokine Knockouts was published, several factors have contributed
to expand the use of gene-deficient mice in research. Advances in molecular biology
techniques have facilitated gene cloning and the building of DNA constructs. Further-
more, the possibility of generating conditional or tissue-specific knockouts, as well as
knock-in mice, has opened new avenues for more sophisticated use of gene-modified
animals in research. At the same time, many universities and research centers have orga-
nized core laboratories for the generation of knockout and transgenic mice, therefore
making this technique available even to nonexperts. These two factors have contributed
to the incredibly rapid increase in the number of new knockout mice created every year
and have led to a marked reduction in the time between the cloning of a new gene and
generating the corresponding deficient mouse, thus speeding up the appreciation of the
in vivo role of any given new gene. The commercial availability of several strains of
gene-deficient mice has been the third factor greatly contributing to widening the use of
knockout mice. After an initial characterization, a large number of investigators decided
to make their mice available through commercial providers. This choice has allowed
laboratories without expertise in molecular biology, but oftentimes with a great deal of
knowledge in the characterization of in vivo processes, to have easy access to gene-
deficient mice. In this way, a sort of long-distance collaboration has narrowed the gap
between molecular biology and in vivo studies, a much appreciated result given the ever
increasing technical specialization of many laboratories. Approximately 10% of the more
than 300 different types of knockout mice that are currently commercially available is
represented by cytokine- or cytokine receptor-deficient mice.
Research in the closely intertwined fields of immunology, infection, and inflam-
mation is proceeding at a pace faster than ever before. Among the many types of media-
tors involved in the regulation of phenomena as varied as resistance to infectious
pathogens, fever, pain, wound healing, autoimmune reactions, hematopoiesis, angio-
genesis, and tumor surveillance—to cite only a few—the family of cytokines can, with-
out any doubt, be considered one of the most prominent. Paraphrasing an Italian saying,
“Cytokines are like parsley,” you can find them everywhere. In fact, as attested by the
reviews collected in this volume, the variety of physiological and pathological condi-
tions in which cytokines have been implicated is staggering. Thanks to the factors men-
tioned above, the use of cytokine knockouts in research has literally exploded in the past
5 to 10 years. A PubMed search with the terms “cytokine” and “knockout mice” pro-
vides a list of approximately 4000 scientific reports, more than 3000 of which were
published since 1998, the year of the first edition of Cytokine Knockouts.
As the reader will appreciate, several new types of cytokine knockout mice have
been generated since the first edition was published. Thus, to cite only a few examples,

ix
x Preface

osteoprotegerin (or RANK) ligand, a major player in bone metabolism and one of the
most promising cytokines in terms of therapeutic developments, had just been cloned
when the first edition of Cytokine Knockouts appeared; the generation of RANK and
RANK- ligand-deficient mice soon followed (see Chapter 23). Despite the long history
of Interleukin (IL)-1, reports describing the generation of IL-1α and double IL-1α/IL-
1β knockouts were only published in 1998, the same year of the first report on IL-18-
deficient mice (see Chapters 6 and 18). Moreover, novel important data have been
published by investigators studying new phenomena in “old” knockouts. To cite only
a few examples, the critical role for IL-1Ra in maintaining control of inflammatory
responses had been reported by two separate groups in 2000 (see Chapter 7), a more
detailed characterization of the pathogenesis of colitis development in IL-2- and IL-10-
deficient mice appeared over the course of the past 5 years (see Chapter 14), the role of
tumor necrosis factor-α and lymphotoxin in the development of germinal centers has
been further clarified (see Chapter 25), and so have the roles of IL-2, IL-7 and the
common γ chain of their receptor in lymphopoiesis (Chapters 8 and 9). From these and
the many more examples that might have been listed, it is clear that the time is right for
a new edition of Cytokine Knockouts.

Structure of the Volume

Cytokine Knockouts is comprised of two sections, Cytokine Knockouts in Models
of Human Disease, and Cytokine Knockout Mice. Although both sections are addressed
to researchers interested in the field of cytokines, Part I could also serve as an introduc-
tion to the use knockout mice for scientists who are not familiar with cytokine research.
Part I contains chapters dedicated to the use of cytokine knockout mice in differ-
ent fields of research. Rather than providing a comprehensive overview of results
obtained using each available knockout mouse, the intent of this first set of reviews is
to present a constructive discussion of ways in which cytokine knockout mice have
been employed in various fields, with clarification of the relative advantages and dis-
advantages of their use.
Several important points are raised by the authors of these chapters. Thus, the reader
is reminded of how the use of different experimental models is subject to the “fashion”
of the moment, so that novel cytokines or novel cytokine-deficient mice are rarely tested
for “old” parameters of pro-inflammatory activities, such as induction of fever. At the
same time, it is critical to use caution when trying to interpret data derived from differ-
ent studies, given the variability of results obtained using apparently similar experimen-
tal models. We also need to use caution when trying to directly infer results for clinical
practice, and avoid creating misleading interpretations. When dealing with knockout
mice, researchers should always take into account the possible effects of redundancy
and of unspecific perturbations of the immune (and other) systems when a single gene is
deleted. The importance of crossing gene-deficient animals into different background
strains appropriate for the study of various conditions is also touched upon in Part I. I
am sure this section will be a helpful tool to stimulate reflection and discussion about
research methodology and data interpretation.
Part II includes chapters dealing with individual cytokines. To avoid excessive
repetition, some cytokines are grouped and presented in families. Similarly, to provide
the reader with a “concentrated” source of information, mice knockouts for a given
Preface xi

cytokine are generally discussed together with mice knockouts for that cytokine’s
receptor(s). Rather than presenting a brief summary of each of the chapters contained in
Part II, I will point out how many unexpected discoveries were made possible by the use
of cytokine knockout mice, and of gene-deficient models in general. Given the extreme
pleiotropy and functional redundancy of many cytokines, it was only after the genera-
tion of mice deficient for each cytokine and each cytokine receptor that the specific in
vivo role of a given molecule could be determined. As detailed in the various chapters,
almost without exception there were big surprises awaiting investigators studying cytokine
knockout mice. New phenotypes are being continually discovered, and some of them do
not apparently have a relationship with immune responses, such as the recently described
spontaneous obesity of IL-6 knockout mice (see Chapter 13). When working with
cytokine-deficient mice, thus, one has to keep an open mind, be a careful observer and
be ready to share results and materials with researchers in other disciplines. When these
measures are carried out, cytokine knockout mice laboratories flourish and important
results can quickly reach an eager audience.
Giamila Fantuzzi, PhD
Contents

Foreword ............................................................................................................................ v
Preface ............................................................................................................................... ix
List of Contributors ....................................................................................................... xvii

PART I. CYTOKINE KNOCKOUTS IN MODELS OF HUMAN DISEASE

1. Cytokine Knockouts in Inflammation
Pietro Ghezzi .................................................................................................. 3
2. The Use of Cytokine Knockouts
to Study Host Defense Against Infection
Charles A. Dinarello ................................................................................... 11
3. The Use of Cytokine Knockouts
in Animal Models of Autoimmune Disease
Alfons Billiau, Hubertine Heremans,
and Patrick Matthys ................................................................................ 33
4. The Use of Cytokine Knockout Mice
in Cancer Research
Robert H. Wiltrout, Jon M. Wigginton,
and William J. Murphy ........................................................................... 57
5. The Use of Cytokine Knockout Mice
in Neuroimmunology
Giamal N. Luheshi, Emmanuel Pinteaux,
and Hervé Boutin .................................................................................... 73

PART II. CYTOKINE KNOCKOUT MICE

6. The Role of IL-1 in the Immune System
Susumu Nakae, Reiko Horai, Yutaka Komiyama, Aya Nambu,
Masahide Asano, Akio Nakane, and Yoichiro Iwakura ...................... 95
7. IL-1 Receptor Antagonist-Deficient Mice
Martin J. H. Nicklin and Joanna Shepherd ........................................... 111
8. A Unique Role for IL-2 in Self-Tolerance
Thomas Hünig and Anneliese Schimpl ................................................... 135
9. Molecular Basis for Binding Multiple Cytokines by γc:
Implications for X-SCID and Impaired γc-Dependent
Cytokine Receptor Function
Ferenc Olosz and Thomas R. Malek ....................................................... 151

xiii
xiv Contents

10. G-CSF, GM-CSF, and IL-3 Knockout Mice

Thomas Enzler and Glenn Dranoff ......................................................... 171

11. IL-4 Knockout Mice

Pascale Kropf and Ingrid Müller ............................................................. 187
12. Role of IL-5 in Immune and Pathological Responses in the Mouse
Paul S. Foster and Simon P. Hogan ........................................................ 203
13. IL-6 Knockout Mice
Valeria Poli and Diego Maritano ............................................................. 213
14. IL-10 and IL-2 Knockout Mice:
Effect on Intestinal Inflammation
Karen L. Madsen and Humberto Jijon ................................................... 237
15. IL-12-Deficient Mice
Luciano Adorini ........................................................................................ 253
16. IL-13 and Double IL-4/IL-13 Knockout Mice
Duncan R. Hewett and Andrew N. J. McKenzie .................................... 269
17. IL-15: Insights from Characterizing IL-15-Deficient Mice
Pallavur V. Sivakumar, Sandra N. Brown,
Ananda W. Goldrath, Anne Renee Van der Vuurst de Vries,
Joanne L. Viney, and Mary K. Kennedy ............................................. 281
18. IL-18 and IL-18 Receptor Knockout Mice
Hiroko Tsutsui, Tomohiro Yoshimoto, Haruki Okamura,
Shizuo Akira, and Kenji Nakanishi..................................................... 303
19. Mice Knockouts for Chemokines and Chemokine Receptors
Jane M. Schuh, Steven L. Kunkel, and Cory M. Hogaboam ................ 323
20. IFN-γ and IFN-γ Receptor Knockout Mice
Dyana Dalton ............................................................................................. 347
21. Macrophage Migration Inhibitory Factor (MIF)-Deficient Mice
Gunter Fingerle-Rowson, Abhay R. Satoskar,
Richard Bucala ..................................................................................... 361
22. Osteopontin, a Surprisingly Flexible Cytokine:
Functions Revealed from Osteopontin Knockout Mice
Susan R. Rittling, Anthony W. O’Regan, and Jeffrey S. Berman ........ 379
23. RANKL, RANK, and OPG
Young-Yun Kong and Josef M. Penninger .............................................. 395
24. Targeting the TGF-β Pathway In Vivo:
Defining Complex Roles for TGF-β Signaling
in Immune Function, Wound Healing, and Carcinogenesis
Lawrence Wolfraim, Mizuko Mamura,
Anita Roberts, and John J. Letterio .................................................... 421
Contents xv

25. Physiologic Roles of Members of the TNF and TNF Receptor

Families as Revealed by Knockout Models
Sergei A. Nedospasov, Sergei I. Grivennikov,
and Dmitry V. Kuprash ......................................................................... 439
Index ............................................................................................................................... 461
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