RECOMBINANT MURINE GAMMA-INTERFERON STIMULATES MACROPHAGES OF THE RAWCELL-LINE TO INHIBIT INTRACELLULAR GROWTH OF HISTOPLASMA-CAPSULATUM

Macrophages of the RAW 264.7 cell line, activated by pretreatment with recombinant murine gamma interferon, inhibit the intracellular growth of Histoplasma capsulatum. Growth inhibition occurred by a mechanism that was operative only when L-Arg metabolism was allowed to occur. Wh en activated macrophages were cultured in the absence of L-Arg or in t he presence of N-G-monomethyl-L-Arg, a competitive inhibitor of L-Arg metabolism, activation to the antihistoplasma growth-inhibitory state did not occur. An increase in levels of NO2-, an end product of L-Arg metabolism, was detected only after activation of RAW 264.7 cells to t he growth-inhibitory state. In contrast, only baseline levels of NO2- were detected when L-Arg was excluded or when N-G-monomethyl-L-Arg was added to the culture medium. Nitric oxide (NO .), a reactive intermed iate product of L-Arg metabolism, was implicated as the relevant antih istoplasma effector molecule. When H. capsulatum yeast cells were cult ured for 24 to 28 h in a system designed to generate soluble NO ., a d ose-dependent cytotoxic effect was observed.