Role of tryptophan degradation in respiratory burst-independent antimicrobial activity of gamma interferon-stimulated human macrophages

Abstract

To determine whether extracellular tryptophan degradation represents an oxygen-independent antimicrobial mechanism, we examined the effect of exogenous tryptophan on the intracellular antimicrobial activity of gamma interferon (IFN-y)-stimulated human macrophages. IFN-y readily induced normal monocyte-derived macrophages (MDM) to express indoleamine 2,3-dioxygenase (IDO) activity and stimulated MDM, alveolar macrophages, and oxidatively deficient chronic granulomatous disease MDM to degrade tryptophan. All IFN-y-activated, tryptophan-degrading macrophages killed or inhibited Toxoplasma gondii, Chlamydia psiuci, and Leishmania donovani. Although exogenous tryptophan partially reversed this activity, the increases in intracellular replication were variable for normal MDM (T. gondii [5-fold], C. psittaci [3-fold], L. donovani [2-fold]), chronic granulomatous disease MDM (T. gondii [2.5-fold], C. psittaci [5-fold]), and alveolar macrophages (T. gondii [1.5-fold], C. psittaci [1.5-fold]). In addition, IFN-a and IFN-I also stimulated normal MDM to express IDO and degrade tryptophan but failed to induce antimicrobial activity, and IFN-,y-treated mouse macrophages showed neither IDO activity nor tryptophan degradation but killed T. gondii and L. donovani. These results suggest that while tryptophan depletion contributes to the oxygen-independent antimicrobial effects of the activated human macrophage, in certain cytokine-stimulated cells, tryptophan degradation may be neither sufficient nor required for antimicrobial activity.

Regulation of the Kynurenine Metabolic Pathway by Interferon‐γ in Murine Cloned Macrophages and Microglial Cells

“…In addition, our data provide a further example of the differences existing between brain microglia and macrophages of peripheral origin in their specific functions in response to immune stimuli. In contrast to other reports (Murray et al, 1989), which failed to detect any IDO activity in murine macrophages on stimulation with IFN-y, we report here that IDO is induced by this cytokine in murine macrophages and microglial cells. Although variations may exist among the cell lines studied, a recent report has shown that peritoneal macrophages from the mouse are able to catabolize L-tryptophan to L-kynurenine on IFN-y treatment, an effect that was particularly evident in the presence of NO synthase inhibitors (Thomas et al, 1994;see below).…”

Granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces toxoplasmastatic activity of human monocytes via induction of prostaglandin E2 (PGE2)

“…In addition, we found that human monocytes did not release NO2^ after infection with T. gondii (data not shown). Tryptophan degradation contributes to the antimicrobial activity of IFN-7-activated human MDM toward T. gondii, but this is not the case for human monocytes [20].…”

Feast or famine: the host-pathogen battle over amino acids

“…In addition to general amino acid depletion, host cells can also specifically deplete intracellular tryptophan during pathogen invasion (Hayashi et al, 2001;Silva et al, 2002). Tryptophan depletion as an anti-bacterial mechanism was first described in Chlamydia-infected cells (Byrne et al, 1986;Murray et al, 1989;Beatty et al, 1994). The addition of interferon-gamma (IFN-g) to infected cells almost completely abolishes intracellular chlamydial growth.…”

“…Early investigations on the role of tryptophan and IDO in driving aberrant form differentiation yielded mixed results. While some groups found tryptophan supplementation alone could reverse the effects of IFN-g, others found no effect (Murray et al, 1989). When the C. trachomatis genome was sequenced -and especially when multiple clinical strains were sequenced -a major clue emerged.…”