Human alveolar and peritoneal macrophages mediate fungistasis independently of L-arginine oxidation to nitrite or nitrate
Human alveolar macrophages (HAM) from 28 normal volunteers were found to inhibit replication of Cryptococcus neoformans. Conditions under which fungistasis occurred were different than those required for mouse peritoneal macrophage-mediated fungistasis. Inhibition of fungal replication by mouse peritoneal macrophages (MPM) requires that the macrophages are activated and that the cocultures of C. neoformans and macrophages be done in the presence of serum, L-arginine, and endotoxin. During MPM-mediated fungistasis and tumor cell killing, L-arginine is oxidized to NO-/2, NO-/3, and L-citrulline. In addition, MPM have arginase activity that converts L-arginine to L-ornithine and urea. HAM-mediated fungistasis was similar to that mediated by MPM in terms of the serum requirement, but HAM did not require L-arginine or endotoxin. HAM did not produce NO-/2or NO-/3detectable by colorimetric and bioassay, nor did HAM produce L-citrulline or L-ornithine from14C-radiolabeled L-arginine as detectable by reverse-phase ion-pairing HPLC of macrophage-C. neoformans coculture supernatants. HAM had no detectable arginase activity, hence there was no evidence for L-arginine nitrogen metabolism in HAM. HAM-mediated fungistasis was not enhanced by endotoxin or by recombinant human interferon-γ (rHIFN-γ). The combination of endotoxin and rHIFN-γ inhibited the fungistatic effect of HAM. Human peritoneal macrophages (HPM) from women undergoing laparoscopy were tested for fungistasis and L-arginine nitrogen oxidation. Partial inhibition of cryptococcal replication occurred; however, there was no evidence of L-arginine metabolism to NO-/2or NO-/3. The absence of L-arginine-dependent nitrogen oxidation in HAM and HPM, compared to MPM, during conditions under which fungistasis occurs suggests that this phenomenon is species specific rather than specific to the tissue origin of the macrophages.
Cameron, ML; Granger, DL; Weinberg, JB; Kozumbo, WJ; Koren, HS
Volume / Issue
Start / End Page
International Standard Serial Number (ISSN)
Digital Object Identifier (DOI)