Alveolar Macrophage - Nitric Oxide

Nitric Oxide

NO is a major source of immunomodulation in rodents, and is produced by enzyme nitric oxide synthetase type 2 (NOS2) in the alveolar macrophage. NO inhibits tyrosine phosphorylation of the kinases involved in production of the interleukin-2 (IL-2) receptor, the expression of which is fundamental for T cell proliferation. In humans, however, NOS2 activity has been difficult to verify.

There are two explanations for the lack of responsiveness in the promoter of human inducible nitric oxide synthetase (iNOS) to NO activation by lipopolysaccharides (LPS) + interferon-gamma (IFN-γ). The first is that there are various inactivating nucleotide variations in the human counterpart of the enhancer element that regulates LPS/IFN-γ induced expression of the mouse NOS2 gene. The second is because of the absence of a nuclear factor in human macrophages that is required for optimum expression of gene NOS2 (LPS-inducible nuclear factor-kappa B/Rel complex). It is assumed that the difficulty in verifying NOS2 is due to a much more tightly controlled expression in human AMs as compared to that in the rodent AMs. NOS2 is part of an autoregulatory feedback loop, wherein an allergen or provoker stimulates inflammatory cytokine production, which in turn stimulates NO production, and NO down-regulates cytokine production. In rats, NO inhibits the granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated maturation of dendritic cells, and in humans it inhibits the TNF-alpha-mediated maturation of human dendritic cells, through cyclic GMP-dependent mechanisms. NO prolongs the ability of human dendritic cells to internalize antigens at sites of inflammation, therefore modulating the beginning steps leading to antigen-specific immune responses.

NO production has been implicated as relevant to the pathology of asthma. Patients with asthma show an increased expression of iNOS in airway epithelial cells and an increased level of nitric oxide in exhaled air.