Amphotericin B Selectively Stimulates Macrophages from High Responder Mouse Strains

Abstract

Lymphoid cells from most inbred mouse strains respond to amphotericin B (AmB)-induced immunostimulation. However, C57BL/6 mice and related strains display low or absent lymphoid cell stimulation by AmB and enhanced susceptibility to AmB toxicity. Experiments reported here show that in vitro incubation with AmB can stimulate AKR (AmB-high responder strain) macrophage proliferation. Intraperitoneal injection of AKR mice with AmB also elicits a population of macrophages primed for enhanced oxidative burst activity after triggering by zymosan particles. Under the same experimental conditions, AmB elicits a population of very weakly responsive macrophages from C57BL/6 mice. The low responsiveness of C57BL/6 macrophages correlates with previous observations that AmB is a potent immunoadjuvant and B cell mitogen in most inbred strains, but it selectively lacks immunoadjuvant effects in C57BL/6 mice and it also fails to induce polyclonal B cell stimulation in their spleen cell suspensions. Similarly, in measurements of protein synthesis in vitro, high concentrations of AmB produce a greater inhibition of protein synthesis in C57BL/6 peritoneal macrophages than in parallel cultures of AKR macrophages. These findings support the hypothesis that the macrophage is an important target cell in the mediation of AmB-induced immunomodulation.

Topical treatment with nanoliposomal Amphotericin B reduces early lesion growth but fails to induce cure in an experimental model of cutaneous leishmaniasis caused by Leishmania mexicana

“…It is known that, in addition to direct effects on the Leishmania parasite, Amphotericin B potentiates the anti-parasitic activity of immune cells either directly or through the production of cytokines (Cleary et al, 1992; Wilson et al, 1991; Wolf et al, 1991). For example, recent studies showed that intravenous administration of Amphotericin B induced Delayed Type Hypersensitivity (DTH) responses, proliferation of lymphocytes, and production of IFN-γ in L. donovani infected mice (Banerjee et al, 2008), as well as induction of Th1 immune responses in patients treated for mucocutaneous leishmaniasis (Cuna et al, 2007).…”

Immunocompromised Hosts: Immunopharmacology of Modern Antifungals

“…Clinically, the proinflammatory activity of AmB-D is associated with acute infusionrelated toxicity, manifesting as rigor, chills, myalgia, and fevereffects that have been shown to correlate with increased blood levels of inflammatory cytokines [7]. Mononuclear cells and neutrophils exposed in vitro to AmB-D rapidly release a variety of inflammatory cytokines (TNF-a, IL-6, IL-1RA, and IL-1b), chemokines (IL-8, MCP-1, and MIP-1b), nitric oxide, prostaglandins, reactive oxygen intermediates, and intercellular adhesion molecule 1 [8,9,15,83]. Stimulation of innate immune cells by AmB is mediated through TLR2 and CD14 and involves a signaling cascade that includes the adapter protein MyD88 and nuclear factor kB, culminating in the up-regulation of genes encoding for inflammatory cytokines [10].…”

Amphotericin B both inhibits and enhances T-cell proliferation: Inhibitory effect is mediated through H2O2 production via cyclooxygenase pathway by macrophages

“…Such a bidirectional effect of the antibiotic was also seen in murine L cells [Brajtburg et al, 1984]. It has been shown that mice strains in which AmB is an immunoadjuvant has a higher level of catalase activity in spleen cells, macrophages, and hepatocytes, as compared with mice in which the drug is immunosuppressive [Stein et al, 1987;Wolf et al, 1991]. Interestingly, it has been reported that a nontoxic thiol derivative of AmB induced a strong proliferative and IgG secretion response under conditions in which the parent AmB is toxic [Sarthou et al, 1986].…”

“…In addition to stimulating PGE 2 production, AmB has been shown to stimulate or enhance the production of superoxide anion (O 2 Ϫ ) in murine macrophages [Stein et al, 1987;Wilson et al, 1991;Wolf et al, 1991] and to involve H 2 O 2 production, inducing injury to lung tissue [Mc-Donnell et al, 1988]. Further, the immune cells from mice in which AmB is either an immunoadjuvant or is ineffective have high catalase activity [Stein et al, 1987], prompting us to explore the possible involvement of H 2 O 2 in mediating the antiproliferative effect of AmB, by examining the effect of exogenously added catalase in this process.…”