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PMID: 9746609 Published · ppublish English Journal Article

Interleukin-12 is essential for a protective Th1 response in mice infected with Cryptococcus neoformans.

Infection and immunity ·Vol. 66 ·No. 10 ·1998-10-00 ·Pages 4994-5000

Decken K, Köhler G, Palmer-Lehmann K, Wunderlin A, Mattner F, Magram J, Gately MK, Alber G

Abstract

To analyze the roles of interleukin-12 (IL-12) and the IL-12-dependent Th1 response in resistance to Cryptococcus neoformans, we have established a chronic infection model in wild-type mice and in mice with targeted disruptions of the genes for the IL-12p35 and IL-12p40 subunits (IL-12p35(-/-) and IL-12p40(-/-) mice, respectively) as well as in mice with a targeted disruption of the IL-4 gene. Long-term application of exogenous IL-12 prevented death of infected wild-type mice for the entire period of the experiment (up to 180 days) but did not resolve the infection. Infected IL-12p35(-/-) and IL-12p40(-/-) mice died significantly earlier than infected wild-type mice, whereas infection of IL-4-deficient mice led to prolonged survival. Interestingly, infected IL-12p40(-/-) mice died earlier and developed higher organ burdens than IL-12p35(-/-) mice, which, for the first time in an infection model, suggests a protective role of the IL-12p40 subunit independent of the IL-12 heterodimer. The fungal organ burdens of IL-4-deficient mice and IL-12-treated wild-type mice were significantly reduced compared to those of untreated wild-type mice and IL-12-deficient mice. Histopathological analysis revealed reduction of the number of granulomatous lesions following treatment with IL-12. Susceptibility of both IL-12p35(-/-) and IL-12p40(-/-) mice was associated with marginal production of gamma interferon and elevated levels of IL-4 from CD4(+) T cells, which indicates Th2 polarization in the absence of IL-12, whereas wild-type mice developed a Th1 response. Taken together, our data emphasize the essential role of IL-12 for protective Th1 responses against C. neoformans.

MeSH Terms
Animals Brain/microbiology,pathology CD4-Positive T-Lymphocytes/immunology Chronic Disease Cryptococcosis/immunology,mortality Disease Models, Animal Granuloma Interferon-gamma/metabolism Interleukin-12/deficiency,immunology Interleukin-4/deficiency,immunology,metabolism Liver/microbiology,pathology Lung/microbiology,pathology Mice Mice, Mutant Strains Spleen/immunology,microbiology,pathology Th1 Cells/immunology Th2 Cells/immunology
Chemicals
Interleukin-12 Interleukin-4 Interferon-gamma
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Decken K
Department of Infectious Diseases, F. Hoffmann-La Roche AG, Basel, Switzerland.
Köhler G
Palmer-Lehmann K
Wunderlin A
Mattner F
Magram J
Gately M K
Alber G
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48 references, click to expand
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Article Info
Journal
Infection and immunity
Abbr.
Infect Immun
ISSN
0019-9567
DOI
10.1128/IAI.66.10.4994-5000.1998
Published
1998-10-00
Pages
4994-5000
Language
English
Region
United States
NLM ID
0246127
PMCID
PMC108620
Subset
IM
External Links
PubMed source DOI: 10.1128/IAI.66.10.4994-5000.1998 PMC Full Text View journal details
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