Enhanced viral clearance in interleukin-18 gene-deficient mice after pulmonary infection with influenza A virus.
T helper 1 driven immune responses facilitate host defence during viral infections. Because interleukin-18 (IL-18) mediates T helper 1 driven immune responses, and since mature IL-18 is up-regulated in human macrophages after influenza virus infection in vitro, it has been suggested that IL-18 plays an important role in the immune response to influenza. To determine the role of IL-18 in respiratory tract infection with influenza, IL-18 gene-deficient (IL-18(-/-)) and normal wildtype mice were intranasally inoculated with influenza A virus. Influenza resulted in an increase in constitutively expressed IL-18 in the lungs of wildtype mice. The clearance of influenza A was inhibited by IL-18, as indicated by reduced viral loads on day 8 and day 12 after infection in IL-18(-/-) mice. This enhanced viral clearance correlated with increased CD4(+) T-cell activation in the lungs as reflected by CD69 expression on the cell surface. Surprisingly, interferon-gamma (IFN-gamma) levels were similar in the lungs of IL-18(-/-) mice and wildtype mice. Intracellular IFN-gamma staining revealed similar expression levels in lung-derived natural killer cells, CD4(+) and CD8(+) T cells, indicating that IFN-gamma production is IL-18-independent during influenza virus infection. Tumour necrosis factor-alpha production by CD4(+) T cells was significantly lower in IL-18(-/-) mice than in wildtype mice. Our data indicate that endogenous IL-18 impairs viral clearance during influenza A infection.
Van Der Sluijs
Koenraad F
KF
Laboratory of Experimental Internal Medicine, University of Amsterdam, Amsterdam, the Netherlands.
Van Elden
Leontine J R
LJ
Arens
Ramon
R
Nijhuis
Monique
M
Schuurman
Rob
R
Florquin
Sandrine
S
Kwakkel
Joan
J
Akira
Shizuo
S
Jansen
Henk M
HM
Lutter
René
R
Van Der Polls
Tom
T
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D007108:Immune Tolerance; D009980:Influenza A virus; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D015996:Survival Rate; D015854:Up-Regulation; D019562:Viral Load
D016207:Cytokines; D020382:Interleukin-18; D012333:RNA, Messenger; D007371:Interferon-gamma