Interferon-gamma (IFN-gamma)-dependent protection and synthesis of chemoattractants for mononuclear leucocytes caused by IL-12 in the lungs of mice infected with Cryptococcus neoformans.
We have recently demonstrated that IL-12 induced cellular inflammatory responses consisting mainly of accumulation of mononuclear leucocytes in the lungs of mice infected with Cryptococcus neoformans and protected mice against fulminant infection. We examined the involvement of endogenously synthesized IFN-gamma in such a response by investigating the effects of a neutralizing monoclonal antibody against this cytokine. The latter treatment completely abrogated the positive effects of IL-12 on survival of infected mice and prevented IL-12-induced elimination of microbials from the lungs. Histopathological examination showed that accumulation of mononuclear leucocytes in the infected lungs caused by IL-12 was clearly inhibited by anti-IFN-gamma MoAb. We also examined the local production of mononuclear cell-attracting chemokines such as monocyte chemotactic protein-1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta and IFN-gamma-inducible protein 10 (IP-10) in the lungs using a reverse transcriptase-polymerase chain reaction (RT-PCR) method. We found that these chemokines were not synthesized in the infected lungs, while IL-12 treatment markedly induced their production. Interestingly, neutralizing anti-IFN-gamma MoAb strongly suppressed IL-12-induced production of these chemokines. Similar results were obtained with MCP-1 and MIP-1alpha when their synthesis was measured at the protein level using respective ELISA kits. Our results indicate that IFN-gamma plays a central role in the protective effects of IL-12 by inducing mononuclear leucocyte-attracting chemokines and cellular inflammatory responses.
First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
K
K
Kawakami
M H
MH
Qureshi
T
T
Zhang
Y
Y
Koguchi
K
K
Shibuya
S
S
Naoe
A
A
Saito
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018932:Chemokine CCL2 / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000378:metabolism; D002630:Chemotactic Factors / Q000096:biosynthesis*; D002634:Chemotaxis, Leukocyte; D003453:Cryptococcosis / Q000276:immunology* / Q000517:prevention & control; D003455:Cryptococcus neoformans / Q000302:isolation & purification; D005260:Female; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000517:prevention & control; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000911:Antibodies, Monoclonal; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D019402:Macrophage Inflammatory Proteins; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma