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From the Departments of Pathology,*
Microbiology,
and
Pediatrics,§
University of Brescia, Brescia and
the Department of Pathology,
University of
Verona, Verona, Italy
Inducible nitric oxide synthase (iNOS) is required in immune
response against infections and is involved in granuloma formation in
animals; in murine macrophages, iNOS is induced by
lipopolysaccharide and interferon-
. In contrast, the role of
iNOS in human immune response against infections is still
questioned, and its expression in granulomas is poorly
investigated. Using Western blotting and immunohistochemistry,
we investigated iNOS expression in human lymph nodes with nonspecific
reactions and in tissues containing granulomas caused by
mycobacteria, Toxoplasma,
Cryptococcus neoformans,
Leishmania, Bartonella,
noninfectious granulomas (sarcoidosis, foreign body),
and other hystiocitic reactions (Kikuchi's disease, Omenn
syndrome). iNOS was undetectable in nonspecific reactive
lymphadenitis, foreign-body granulomas, and Omenn
syndrome, whereas it was strongly expressed in infectious
granulomas, sarcoidosis, and Kikuchi's diseases.
Immunohistochemistry demonstrated that iNOS was selectively expressed
by the epithelioid and multinucleated giant cells within the
granulomas. Use of an anti-nitrotyrosine antibody, recognizing
nitrosilated amino acid residues derived from nitric oxide
production, revealed a consistent positivity within the cells
expressing iNOS, thus suggesting that iNOS is functionally
active. Detection of cytokines by reverse transcriptase-polymerase
chain reaction demonstrated that tissues that were positive for
iNOS, also expressed the Th1-type cytokine interferon-
mRNA, but not the Th2-type cytokine interleukin-4. Taken
together, these results indicate that iNOS is involved in
different human immune reactions characterized by
histiocytic/granulomatous inflammation and associated with Th1-type
cytokine secretion.
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