IL-1 in Disseminated Candidiasis
• JID 2006:193 (15 May) • 1419
M A J O R A R T I C L E
Endogenous Interleukin (IL)–1a and IL-1b Are
Crucial for Host Defense against Disseminated
Alieke G. Vonk,1,3Mihai G. Netea,1,3Johan H. van Krieken,2Yoichiro Iwakura,4Jos W. M. van der Meer,1,3
and Bart Jan Kullberg1,3
Nijmegen, The Netherlands;
2Pathology, Radboud University Nijmegen Medical Center, and
4Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
3Nijmegen University Center for Infectious Diseases,
against Candida albicans. It is, however, unknown whether they provide protection through similar mechanisms.
We investigated the effect of endogenous IL-1a and IL-1b on disseminated C. albicans infection.
Mice deficient in the genes encoding IL-1a (IL-1a?/?), IL-1b (IL-1b?/?), or both molecules (IL-
1a?/?b?/?) were used. Survival and C. albicans outgrowth in the kidneys was assessed after intravenous injection
of C. albicans.
Both mortality and C. albicans outgrowth in the kidneys were significantly increased in IL-1a?/?and
IL-1b?/?mice, compared with those in control mice, with the IL-1a?/?b?/?mice being most susceptible to
disseminated candidiasis. The host defense mechanisms triggered by IL-1a and IL-1b differed from one another.
IL-1b?/?mice showed decreased recruitment of granulocytes in response to an intraperitoneal C.albicanschallenge,
and generation of superoxide production was diminished in IL-1b?/?granulocytes. IL-1a?/?mice had a reduced
capacity to damage C. albicans pseudohyphae. Protective type 1 responses were deficient in both IL-1a?/?and IL-
1b?/?mice, as assessed by production of interferon-g by splenocytes in response to heat-killed C. albicans.
Although IL-1a and IL-1b have differential effects on the various arms of host defense, both
cytokines are essential for mounting a protective host response against invasive C. albicans infection.
Interleukin (IL)–1a and IL-1b are protective proinflammatory cytokines involved in host defense
Despite the availability of potent antifungal agents,
acute disseminated candidiasis remains a life-threat-
ening disease that occurs mainly in immunocompro-
mised patients . Immunotherapies with cytokines
have great potential to augment host resistance and as
adjunctive treatment for invasive candidiasis. For fur-
ther development of these strategies, a better under-
standing of the protective immune mechanismsagainst
invasive candidiasis is needed.
Interleukin (IL)–1a and IL-1b are proinflammatory
cytokines that exert similar biological activities after
Received 5 July 2005; accepted 29 December 2005; electronically published 4
Potential conflicts of interest: none reported.
Financial support: Netherlands Organisation for Scientific Research (VIDI grant
Reprints or correspondence: Dr. Bart Jan Kullberg, Dept. of Medicine (463),
Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500 HB Nijmegen,
The Netherlands (B.Kullberg@aig.umcn.nl).
The Journal of Infectious Diseases
? 2006 by the Infectious Diseases Society of America. All rights reserved.
interaction with the IL-1 type I receptor (IL-1RI) and
the IL-1R accessory protein . Exogenous recombi-
nant human IL-1a or IL-1b has been administered in
studies of disseminated murine candidiasis, and these
studies have clearly indicated a protective role for IL-
1 in this infection model [3, 4]. The mechanisms of
this beneficial effect have been only partly elucidated.
IL-1 has no direct antifungal effect, and the protective
effect of IL-1 in host defense against Candida albicans
does not depend on the presence of granulocytes or
humoral factors, such as acute-phase proteins [3, 4].
To characterize the role of endogenous IL-1a and IL-
1b in disseminated candidiasis and to gain further in-
sight into the mechanisms through which both IL-1
molecules confer protection against disseminated can-
didiasis, mice in which the genes encoding IL-1a (IL-
1a?/?), IL-1b (IL-1b?/?), or both (IL-1a?/?b?/?) had
been disrupted were used in the present study. The IL-
1–deficient mice and their immunocompetent litter-
mates were subjected to experimental disseminated C.
by guest on February 2, 2016
1426 • JID 2006:193 (15 May) • Vonk et al.
We are greatly indebted to Ineke Verschueren, Debby Smits, and Maichel
van Riel, for their help with the experiments.
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