title: High levels of interleukin-10 impair resistance to pulmonary coccidioidomycosis in mice in part through control of nitric oxide synthase 2 expression.
abstract: We have shown previously that there is a direct correlation between IL-10 levels and susceptibility to Coccidioides immitis peritonitis in C57BL/6 (B6), DBA/2, and BXD recombinant inbred mice. We now show that B6 mice are also more susceptible to C. immitis pneumonia and that interleukin-10 (IL-10)-deficient (IL-10-/-) B6 mice are more resistant to C. immitis pneumonia. In addition, we established that high levels of IL-10 are sufficient to make genetically resistant mice susceptible to both C. immitis peritonitis and pneumonia by infecting h.IL-10 transgenic mice. Infected h.IL-10 transgenic mice express lower levels of gamma interferon, IL-12 p40, and inducible nitric oxide synthetase 2 (NOS2) mRNA in their lungs, implicating inducible NOS as a defense mechanism in this disease. We treated DBA/2 mice with aminoguanidine, and they became more susceptible to C. immitis peritonitis and pneumonia. We conclude that high levels of IL-10 are both necessary and sufficient to make mice susceptible to C. immitis, regardless of the genetic background of the mice, and that IL-10 impairs resistance to C. immitis in part by suppressing NO synthesis.
authors.affiliation: Infectious Diseases Section (111F), VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
authors.forename: Maria del Pilar
authors.initials: Mdel P
authors.lastname: Jimenez
authors.forename: Lorraine
authors.initials: L
authors.lastname: Walls
authors.forename: Joshua
authors.initials: J
authors.lastname: Fierer
mesh_terms: D000818:Animals; D003047:Coccidioidomycosis / Q000276:immunology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006146:Guanidines / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics / Q000502:physiology*; D015847:Interleukin-4 / Q000235:genetics; D008172:Lung Diseases, Fungal / Q000276:immunology*; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D006146:Guanidines; C090663:N(6)-(1-iminoethyl)lysine; D012333:RNA, Messenger; D016753:Interleukin-10; D015847:Interleukin-4; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D008239:Lysine; C004479:pimagedine