Research Update
TRENDS in Immunology Vol.22 No.8 August 2001
the sphingosine kinase pathway. Proc. Natl. Acad.
4 Kwak, B. et al. (2000) Statins as a newly
recognized type of immunomodulator. Nat. Med.
specificity and produce side-effects.
5 Proudfoot, A.E. et al. (2000) The strategy of
blocking the chemokine system to combat disease.
6 Reedquist, K.A. et al. (2000) The small GTPase,
Rap1, mediates CD31-induced integrin adhesion.
7 Aurrand-Lions, M.A. et al. (2000) Cloning of
adhesion molecular family? Curr. Top. Microbiol.
8 Risau, W. et al. (1998) Differentiation of
blood–brain barrier endothelial cells. Pathol. Biol.
properties of the BBB are frequently lost,
leukocytes will point to novel therapeutic
specific loss of immunostaining for the TJ
molecule claudin-1 from inflamed cerebral
Beat A. Imhof* Acknowledgements
claudin-5 and other TJ molecules, such as
occludin and ZO-1, was conserved. In an invitro model of the BBB, this selective loss
Britta Engelhardt
of claudin-1 correlates directly with the
the text represents only a small selection
Max-Planck-Institut fur Physiologische und
opening of endothelial TJs (Fig. 1). These
Klinische Forschung, W.G. Kerckhoff-Institut,
References
1 Butcher, E.C. et al. (1999) Lymphocyte trafficking
and regional immunity. Adv. Immunol. 72, 209–253
Mathew A. Vadas Conclusions
2 Johnson-Leger, C. et al. (2000) The parting of the
endothelium: miracle, or simply a junctional
affair? J. Cell Sci. 113, 921–933
3 Xia, P. et al. (1998) Tumor necrosis factor α
Medical and Veterinary Science, University of
induces adhesion-molecule expression through
Adelaide, Adelaide, SA 5000, Australia. IL-10 and its homologs: important immune mediators and emerging immunotherapeutic agents
Hans-Dieter Volk, Khusru Asadullah, Grant Gallagher, Robert Sabat and Gerald Grütz
The 3rd International Workshop on IL-10
Phase II clinical trials using recombinant
and Related Molecules was held at Charité
inflammatory cytokine initially, but recent
Berlin, Germany from 4–7 April 2001.
safety and efficacy of this therapy for all of
complex characteristics. In addition, novel
positive response to treatment with IL-10
was observed for psoriasis (K. Asadullah,
T helper 2 (Th2)-cell clones and inhibits
the synthesis of interferon γ (IFN-γ) by
Th1-cell clones1. Today, this ‘cytokine
The role of IL-10 in disease and its use as a therapeutic agent
IL-10 therapy after the clearance of active
demonstrated for various cell populations,
psoriasis by conventional therapy is very
including certain T-cell subsets [e.g. Th2
http://immunology.trends.com 1471-4906/01/$ – see front matter 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(01)01985-8
Research Update
TRENDS in Immunology Vol.22 No.8 August 2001
(‘immunoparalysis’) contributing to the
high rate of late mortality seen in patients
influence the capacity for the secretion of
have been published on ‘high’- and ‘low’-
are associated with the incidence andseverity of various immune diseases,
Newcastle, UK; A. Vergopoulos, Berlin,Germany; and J. May, Tuebingen,
Fig. 1. The genomic localization of the genes encoding interleukin-10 (IL-10), interferon γ (IFN-γ) and the novel IL-10
homologs on human chromosomes 1 and 12. Abbreviations: AK155, Andrea Knappe 155 gene; MDA-7, melanoma
polymorphisms to facilitate thecomparison of the data (G. Gallagher,
disorders seems to be complex. On the one
IL-10 and regulatory T cells
tumor necrosis factor (TNF) and/or IFN-γ].
as effective and safe in the treatment of
allergen (C. Akdis, Davos, Switzerland).
On the other hand, a lack of effectiveness
of IL-10 or transforming growth factor β
(TGF-β) is thought to be important for the
the different types of allergies and atopic
adenoviral vectors and the difficulties in
important role in the pathogenesis of post-
A. O’Garra (Palo Alto, CA, USA) described
counter-regulation is realized at the level
Research Update
TRENDS in Immunology Vol.22 No.8 August 2001
Table 1. The properties of IL-10-related moleculesa Cellular source Biological effects Receptors
No effects on cytokine synthesis by PBMCs ND
Overexpression in mice causes retardation of
growth and development, skin abnormalities
Application in adult mice induces an acute
phase response and basophilia in proximal
(hepatoma cell lines), inhibition of IL-4
renal tubules; it acts as an autocrine factor for
Melanoma cells, skin fibroblasts Antitumor effects
(induction of apoptosis or differentiation),
aAbbreviations: AK, Andrea Knappe; GM-CSF, granulocyte–macrophage colony-stimulating factor; IL, interleukin; LPS, lipopolysaccharide; MDA, melanoma differentiationassociated gene; ND, not determined; PBMC, peripheral blood mononuclear cell; PHA, phytohemagglutinin; Th, T helper; STAT3, signal transducer and activator of
regulatory T cells in coculture. So far, it
in vitro-generated regulatory T cells
efficiently. The addition of IL-15 (instead
Berlin, Germany). T. Mijatovic (Brussels,
IL-10 signaling and molecular mechanisms of inhibitory function
action of IL-10; their possible inhibition
3′ untranslated region (UTR) of the TNF
there have been conflicting reports about
well as the 5′UTR, seem to be necessary
the molecular basis of this inhibition. The
nuclear translocation of the transcription
factor NF-κB heterodimer is considered to
depend very much on the model used wasdiscussed by B. Foxwell (London, UK). Key outcomes of the meeting
There are obvious differences betweencell lines and primary cells. Both
• IL-10 has been shown to be effective and safe in several clinical trials (e.g. for the
treatment of rheumatoid arthritis) although it was less effective than therapy with
• In the treatment of psoriasis, IL-10 reversed acute disease effectively and prevented
the relapse of disease activity. This might represent a novel approach for therapy with
• It is possible to expand IL-10-driven regulatory T-cell populations in vitro using IL-15,
without the loss of their suppressor function.
• IL-10 upregulates the expression of >300 genes, suggesting the complexity of its signaling.
• Several IL-10 homologs have been described. None of these appear to share the
immunoregulatory and anti-inflammatory properties of IL-10. However, they have
interesting biological activities including: antitumor effects, the induction of
expression of acute-phase proteins and the stimulation of keratinocytes to
showed only the 3′UTR-mediatedinhibition, regardless of the timing of
Research Update
TRENDS in Immunology Vol.22 No.8 August 2001
IL-10-related molecules
(SFB 421). Additional support was provided
mostly as a result of in silico work. At the
which is strongly influenced by signaling
would like to apologize to all speakers whose
groups (R. de Waal Malevyt; G. Gallagher;
the effects of IL-10 (M. Cassatella, Verona,
abstracts of this meeting are published in
Genes and Immunity (2001) 2, 161-179. References
1 Fiorentino, D.F. et al. (1989) Two types of mouse
T helper cell. IV. Th2 clones secrete a factor that
inhibits cytokine production by Th1 clones.
and H. Fickenscher, Erlangen, Germany).
2 Gallagher, G. et al. (2000) Cloning, expression and
dispensable for the activating function of
initial characterisation of interleukin-19 (IL-19),
IL-10 in B cells (B. Weaver, St Louis, MO,
chromosomes one and 12, close to the gene
a novel homologue of human interleukin-10
loci encoding IL-10 and IFN-γ, respectively
(IL-10). Genes Immun. 1, 442–450
(Fig. 1). Three of these homologs [IL-19,
Hans-Dieter Volk* Gerald Grütz
which is dependent on the presence of this
Institute of Medical Immunology, Charité,
Humboldt University Berlin, D-10098 Berlin,
identify the downstream signaling events.
immunosuppressive function of IL-10. Robert Sabat Khusru Asadullah
mRNA analysis to address this question.
important properties of these homologs.
Experimental Dermatology, Muellerstr. 178,
London, UK), but there is a long way to go
Acknowledgements
to prove the function of those genes whose
This meeting was organized by the authors,
Grant Gallagher Keeping up with the Trends
Articles of interest to immunologists in other Trends journals:
Arroyo, J. et al. (2001) Yellow fever vector live-virus vaccines: West Nile virus vaccine development.
Arold, S.T. and Baur, A.S. (2001) Dynamic Nef and Nef dynamics: how structure could explain the complex activities of
Zeh, H.J., III et al. (2001) Vaccines for colorectal cancer.
Khanna, R. et al. (2001) Immunotherapeutic strategies for EBV-associated malignancies.
Imler, J-L. and Hoffmann, J.A. (2001) Toll receptors in innate immunity.
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