Reactions of Nitric Oxide in the Immune System

INTRACELLULAR REACTIONS OF NITRIC OXIDE IN THE IMMUNE SYSTEM 

The study of the biosynthesis of inorganic nitrogen oxides has a long and distinguished history, principally in the field of microbial and plant nitrogen metabolism (Zumft, 1993). Relatively recently, it has been found that NO, in addition to other species such as nitrite, nitrate, and NjO, is a true intermediate in the biological nitrogen cycle, as described in detail in Chapter 9. 

In 1985, Stuehr and Marietta demonstrated that the macrophage is the major source of N02 and NO, in response to LPS, at least in the mouse. Subsequently, this group showed that addition of LPS and the immune cytokine interferon-y (cytokines are discussed in more detail below) to macrophages results in N-nitrosation of morpholine the N-nitrosamine was not formed by addition of NO2 and morpholine to the macrophages, and the highest levels of N-nitrosamine occurred many hours prior to the peak NO2 formation (Miwa et al., 1987). Thus, treated macrophages are stimulated to produce a reactive precursor to N02 and NO,, which is capable of N-nitrosamine formation. 

What is the immunological significance and the mechanism of this stimulation of nitrogen oxide formation in response to bacterial products The answers to these questions originate in an extensive body of medical and immunological literature prior to 1987. 

In 1975, Carswell et al. discovered that this bacterial-induced tumor killing activity could he transferred from one animal to another. When the serum of a mouse that is pretreated with LPS (also called endotoxin) is injected into another animal that has not been treated with endotoxin but harbors a transplantable skin tumor, the tumor undergoes necrosis. In addition, Carswell etal. also showed that addition of this substance (which they dubbed tum .)r necrosis factor, or TNF) to cultures of transformed cells results in death of the cells (Helson ec al., 1975). It is now known that TNF is a member of a class of proteins called cytokines, which are immune hormones, that is, proteins that are secreted by certain immune cells during stimulation. These proteins are extraordinarily important in the immune response, by acting as the messengers between different cells to relay information (Abbas, 1991). 

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The Intracellular Reactions of Nitric Oxide in the Immune System and Its Enzymatic Synthesis... 

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