Expression of inducible nitric oxide synthase in human granulomas and histiocytic reactions

Inducible nitric oxide synthase (iNOS) is required in immune response again st infections and is involved in granuloma formation in animals; in murine macrophages, iNOS is induced by lipopolysacharide and interferon-gamma. In contrast, the role of iNOS inhuman immune response against infections is st ill questioned, and its expression in granulomas is poorly investigated. Us ing Western blotting and immunohistochemistry, we investigated iNOS express ion in human lymph nodes with nonspecific reactions and in tissues containi ng granulomas caused by mycobacteria, Toxoplasma, Cryptococcus neoformans, Leishmania, Bartonella, noninfectious granulomas (sarcoidosis, foreign body ), and other hystiocitic reactions (Kikuchi's disease, Omenn syndrome). iNO S was undetectable in nonspecific reactive lymphadenitis, foreign-body gran ulomas, and Omenn syndrome, whereas it was strongly expressed in infectious granulomas, sarcoidosis, and Kikuchi's diseases. Immunohistochemistry demo nstrated that iNOS was selectively expressed by the epithelioid and multinu cleated giant cells within the granulomas. Use of an anti-nitrotyrosine ant ibody, recognizing nitrosilated amino acid residues derived from nitric oxi de production, revealed a consistent positivity within the cells expressing iNOS, thus suggesting that iNOS is functionally active. Detection of cytok ines by reverse transcriptase-polymerase chain reaction demonstrated that t issues that were positive for iNOS, also expressed the Th1-type cytokine in terferon-gamma mRNA, but not the Th2-type cytokine interleukin-4, Taken tog ether, these results indicate that iNOS is involved in different human immu ne reactions characterized by histiocytic/granulomatous inflammation and as sociated with Th1-type cytokine secretion.