Activation of antimicrobial functions
Monocytes and polymorphonuclear cells possess a number of oxygen-dependent and oxygen-inde-pendent antimicrobial mechanisms. These, while often constitutively expressed, can be activated directly by bacterial products or by cytokines such as IFNy.
Oxygen-dependent pathways: derivatives of superoxide anion Oxygen is reduced by a membrane-associated cytochrome system which transfers an electron onto molecular oxygen to form superoxide anion (O'^), usually during phagocytosis. Subsequent interactions give rise to hydrogen peroxide (H202), hydroxyl radicals (-OH), and perhaps singlet oxygen (A'02), which is oxygen with one electron in a high energy state. These toxic intermediates are generated in the absence of myeloperoxidase (MPO) and therefore do not require fusion of the MPO-con-taining lysosomes with the phagosome. If fusion does occur, MPO catalyzes the formation of hypohalous acids from H202 and halides.
Oxygen-dependent pathways: nitric oxide Nitric oxide (NO) is formed from the guanidino nitrogen of L-arginine, by NO synthase, yielding citrulline as the other product. Formation of NO is enhanced by exposure to IFNy and a trigger of TNFa release such as endotoxin, or the equivalent cytokine triggers of other organisms. The NO is a relaxant of vascular smooth muscle and has poorly understood roles in intracellular signaling. Within macrophages it probably acts as an antimicrobial agent, though such effects are difficult to distinguish from its signaling role. Whatever the mechanism, agents that block NO synthase enhance growth of M. tuberculosis within macrophages both in vivo and in vitro. It is more difficult to make human macrophages generate high levels of NO, but it is now clear that they can do if stimulated with mixtures of cytokines (interleukin 4 (IL-4) and IFNy) or further triggered by cross-linking CD23.
Some oxygen-independent killing may be due to the sequential exposure to lysozyme and neutral proteases at pH 7.0-8.0, followed by acid hydrolases after the acidification step, but several more specific pathways have now been defined.
Cationic proteins Human granulocytes contain cat-ionic proteins with microbicidal activity. Six have been sequenced and are cysteine- and arginine-rich peptides of 32-34 amino acids with molecular weights of about 4 kDa. They are representatives of a conserved family of related mammalian 'antibiotics* which have been named 'defensins'. Similar proteins are found in the granules of rabbit alveolar macrophages but not in human macrophages, although these contain other cationic antibacterial substances, some of which are enzymes, which kill gram-positive and -negative bacteria and fungi by mechanisms quite independent of their enzymatic activity. More over, it is likely that the uptake of enzymes and cations from other cells plays a significant role in macrophage antibacterial function in vivo. The defensins will kill organisms as diverse as Staphylococcus aureus, Pseudomonas aeruginosa, E. coli, Cryptococcus neoformans and even the enveloped virus, Herpes simplex.
Tryptophan deprivation Exposure to IFN7 causes degradation of tryptophan in monocytes and fibroblasts. This amino acid is essential for some pathogens.
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