Cytokine networking in lungs of immunocompetent mice in response to inhaled Aspergillus fumigatus.
Cytokine networking in the lung in response to inhaled Aspergillus fumigatus was assessed using a murine model of primary pulmonary aspergillosis in immunocompetent Crl:CF-1 mice. Inhalation of virulent A. fumigatus (6 x 10(6) CFU) resulted in the induction of interleukin 18 (IL-18), tumor necrosis factor alpha (TNF-alpha), IL-12, and gamma interferon (IFN-gamma) protein in bronchoalveolar lavage fluid and/or lung tissue. Induction of immunoreactive IL-18 preceded induction of TNF-alpha protein, which preceded induction of immunoreactive IL-12 and IFN-gamma. Real-time reverse transcriptase (RT) PCR analysis of infected lung tissue demonstrated that induction of IL-18 protein also preceded induction of pulmonary TNF-alpha, IL-12, and IFN-gamma mRNAs. Mice were subsequently treated with cytokine-specific neutralizing monoclonal antibodies (MAbs) to the IL-18 receptor (anti-IL-18R MAb), TNF-alpha (anti-TNF-alpha MAb), IL-12 (anti-IL-12 MAb), and/or IFN-gamma (anti-IFN-gamma MAb), and effects on intrapulmonary cytokine activity and growth of A. fumigatus were assessed in infected lung homogenates. Simultaneous neutralization of IL-12 and IL-18 resulted in decreased levels of immunoreactive TNF-alpha, while neutralization of IL-18, TNF-alpha, or IL-12 alone or of IL-18 and IL-12 together resulted in decreased levels of immunoreactive IFN-gamma. Simultaneous neutralization of IL-12 and IL-18 or neutralization of TNF-alpha alone or in combination with IL-12, IL-18, or IFN-gamma also resulted in a significant increase in A. fumigatus CFU in lung tissue. Taken together, these results demonstrate that endogenous IL-18, IL-12, and TNF-alpha, through their modulatory effects on both intrapulmonary cytokine activity and growth of A. fumigatus, play key roles in host defense against primary pulmonary aspergillosis.
Brieland
J K
JK
Department of Chemotherapy, Schering Plough Research Institute, Kenilworth, New Jersey 07033, USA. joan.brieland@spcorp.com
Jackson
C
C
Menzel
F
F
Loebenberg
D
D
Cacciapuoti
A
A
Halpern
J
J
Hurst
S
S
Muchamuel
T
T
Debets
R
R
Kastelein
R
R
Churakova
T
T
Abrams
J
J
Hare
R
R
O'Garra
A
A
D000276:Adjuvants, Immunologic; D000818:Animals; D001228:Aspergillosis / Q000209:etiology / Q000276:immunology*; D001232:Aspergillus fumigatus / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis*; D007121:Immunocompetence; D007371:Interferon-gamma / Q000032:analysis; D018664:Interleukin-12 / Q000032:analysis; D020382:Interleukin-18 / Q000032:analysis; D008168:Lung / Q000276:immunology*; D008172:Lung Diseases, Fungal / Q000209:etiology / Q000276:immunology*; D008297:Male; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000276:Adjuvants, Immunologic; D016207:Cytokines; D020382:Interleukin-18; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma