IFN-γ is an important mediator of cellular resistance against microbial pathogens and tumor cells due in part to its potent capacity to activate macrophages for enhanced cytotoxicity. The present study demonstrates that TNF-α regulates the expression of enhanced antimicrobial activity by triggering IFN-γ primed macrophages to kill or inhibit intracellular Toxoplasma gondii. Resident mouse macrophages stimulated with rIFN-γ at levels up to 2500 U/ml failed to display enhanced antitoxoplasmal activity when cultured in vitro under low endotoxin conditions (<10 pg/ml), but were triggered by addition of small amounts of LPS (0.1 ng/ml). A similar requirement for LPS as a second signal necessary to trigger antitoxoplasmal activity was observed when IFN-γ was administered to mice in vivo. The essential nature of this triggering step allowed us to explore the role of cytokines that act as endogenous regulators of macrophage activation. rTNF-α, although unable to confer antitoxoplasmal activity when used alone to treat macrophages, was capable of triggering IFN-γ-primed macrophages cultured under low endotoxin conditions. The ability of TNF-α to trigger IFN-γ-primed macrophages was blocked by rabbit anti-TNF-α polyclonal antisera but was not affected by polymyxin B indicating that TNF-α triggering was not due to contamination with LPS. Collectively, these findings demonstrate that TNF-α performs an important regulatory role in the expression of enhanced anti-microbial activity by IFN-γ-primed macrophages.
|Number of pages||6|
|Journal||Journal of Immunology|
|State||Published - 1991|