In 2001, S. Thoma-Uszynski et al. wrote in Science,“in humans the TLR-activated antimicrobial pathway is NO [nitric oxide]-independent”(1). In the Report “Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response”(PT Liu et al., 24 Mar., p. 1770; published online on 23 Feb.), authors from the same laboratories expanded this view to assert that “antimicrobial activity against intracellular bacteria… in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide” and that this establishes “the evolution of divergent antimicrobial pathways in mice… versus humans.…” The conclusion that humans lack this nitric oxide defense pathway in mononuclear phagocytes is based on in vitro findings that differ in a critical respect from observations of human macrophages in vivo and ex vivo. Thoma-Uszynski et al.(1) and Liu et al. cultured human monocytes under conditions that result in little or no expression of inducible NO synthase (iNOS). In contrast, in vivo and ex vivo, human macrophages do express iNOS in people with infectious and inflammatory diseases (2, 3), notably in tuberculosis.

The role of iNOS in human host defense remains unresolved. The experiments (4–6) that established the role of iNOS in host defense in mice cannot be performed in people. However, when macrophages expressing iNOS were recovered from patients and infected with mycobacteria in vitro, iNOS inhibitors abolished the macrophages' antimycobacterial activity (7).