Amphotericin B both inhibits and enhances T-cell proliferation: Inhibitory effect is mediated through H2O2 production via cyclooxygenase pathway by macrophages
✍ Scribed by Sanjeev Kumar; Rabindranath Chakrabarti
- Book ID
- 101262329
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- English
- Weight
- 207 KB
- Volume
- 77
- Category
- Article
- ISSN
- 0730-2312
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✦ Synopsis
Amphotericin B (AmB) has been shown to have both immunosuppressive and -enhancing effects, making its precise nature of action enigmatic. In the present study, we found that AmB inhibited concanavalin A (Con A)-induced T cell proliferation if added within first 30 min of stimulation, after which inhibition began to diminish rapidly. However, AmB did not inhibit T-cell proliferation induced by a combination of PMA and ionomycin. AmB inhibition of Con A-induced proliferation was completely overcome by cyclooxygenase inhibitor ibuprofen ([␣-methyl-4-(isobutyl)phenylacetic acid]) and H 2 O 2 scavenger catalase. In fact, in the presence of ibuprofen and catalase, AmB enhanced, instead of suppressing, Con A-induced proliferation in a dose-dependent way. The effect of catalase was limited to the removal of extracellular H 2 O 2 only, as the enzyme did not enter the cells. AmB stimulated H 2 O 2 production by macrophages, but not by a lymphocyte population, which was inhibited by ibuprofen. Our T-cell preparation contained about 3% macrophages, and AmB inhibition of proliferation was further pronounced by increasing the macrophage number by as little as 1%. Finally, AmB inhibition of Con A-induced T-cell proliferation was completely overcome by 2-mercaptoethanol. On the basis of these results, we suggest that AmB stimulates H 2 O 2 production by macrophages through the activation of the cyclooxygenase pathway of arachidonate metabolism. H 2 O 2 then inhibits Con A-induced T-cell proliferation by interfering with an early step of the T-cell receptor signaling pathway through the oxidative modification of some signaling proteins. Our results also show that AmB enhances T-cell proliferation, which can be seen only after blocking its inhibitory effect.