Involvement of endogenously synthesized interleukin (IL)-18 in the protective effects of IL-12 against pulmonary infection with Cryptococcus neoformans in mice.
We previously demonstrated that interleukin (IL)-12 protected mice against fatal pulmonary infection with a highly virulent strain of Cryptococcus neoformans, which correlated well with the production of interferon (IFN)-gamma as well as IL-18 in the primary infected site. In the present study, we examined the role of endogenously synthesized IL-18 in IL-12-induced host resistance to this pathogen. There was little or no production of IFN-gamma and IL-18 both at mRNA and protein levels in lungs of mice infected with C. neoformans, while treatment with IL-12 induced a marked production of these cytokines. Caspase-1 mRNA was expressed in infected mice even without IL-12 treatment. Administration of neutralizing anti-IFN-gamma monoclonal antibody (mAb) clearly inhibited production of IFN-gamma and IL-18 induced by IL-12, while control IgG did not show such an effect. However, administration of IFN-gamma did not induce the production of both cytokines in infected mice, although tumor necrosis factor (TNF)-alpha and IFN-gamma-inducible protein (IP)-10 were synthesized by the same treatment. Finally, neutralizing anti-IL-18 antibody (Ab) significantly interfered with the production of IFN-gamma and elimination of the microorganism from the lung induced by IL-12 treatment. Furthermore, both IFN-gamma synthesis and host protection caused by IL-12 were profoundly diminished in IL-18 gene-disrupted mice. Considered collectively, our results indicated that host protection against C. neoformans induced by IL-12 involved endogenously synthesized IL-18 and that the production of IL-18 was mediated at least in part by endogenous IFN-gamma.
Kawakami
K
K
First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, Japan. kawakami@med.u-yukyu.ac.jp
Qureshi
M H
MH
Zhang
T
T
Koguchi
Y
Y
Yara
S
S
Takeda
K
K
Akira
S
S
Kurimoto
M
M
Saito
A
A
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D020170:Caspase 1 / Q000096:biosynthesis / Q000235:genetics; D003453:Cryptococcosis / Q000276:immunology* / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000276:immunology / Q000302:isolation & purification; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology* / Q000494:pharmacology; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000382:microbiology; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D012331:RNA, Fungal / Q000032:analysis; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020382:Interleukin-18; D012331:RNA, Fungal; D018664:Interleukin-12; D007371:Interferon-gamma; D020170:Caspase 1