Modulation of inducible nitric oxide synthase activation by immunosuppressive drugs

The activation of inducible form of nitric oxide (NO) synthase (iNOS, type II, or macrophage NOS) and subsequent production of free radical gas NO is an important anti-infectious and anti-tumor mechanism of innate immunity. On the other hand, high amounts of iNOS-derived NO have been implicated in self-tissue destruction during autoimmune diseases, allograft rejection, sepsis, and other disorders accompanied by excessive activation of the immune system. It is generally accepted that beneficial effects of some recently designed immunosuppressive agents primarily stem froin their ability to interfere with the function of T and/or B cells, thus preventing deleterious consequences of specific immunity-innate immunity positive feedback, with high NO production being one of them. However, it has been recently observed that drugs like cyclosporin A, FK506, leflunomide, mycophenolate mofetil, pentoxifylline, and linomide can directly modulate cytokine and/or LPS-induced NO production in various cell types in vitro, probably by interfering with iNOS gene transcription or catalytic activity of iNOS enzyme. Interestingly, some of these drugs exhibited cell-specific pattern of iNOS modulation, thus indirectly revealing distinct requirements for iNOS induction in different cell types. Possible impact of this direct and cell-selective interference with iNOS activation on the therapeutic effectiveness of immunosuppressive drugs is discussed.