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Controls Intracellular Mycobacterial Growth by Both Inducible Nitric Oxide Synthase-Dependent and Inducible Nitric Oxide Synthase-Independent Pathways1
*
The Rockefeller University, New York, NY 10021;
Department of Immunology, Medical School, University of Cape Town, Groote Schuur Hospital, South Africa; and
Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105
The role of TNF-
in the control of mycobacterial growth in
murine macrophages was studied in vitro. Infection of macrophages from
TNF- gene disrupted (TNF-knockout (KO)) mice with recombinant
Mycobacterium bovis bacillus Calmette
Guérin (BCG) expressing the vector only (BCG-vector)
resulted in logarithmic growth of the intracellular bacilli. Infection
with BCG-secreting murine TNF- (BCG-TNF) led to bacillary killing.
Killing of BCG-TNF was associated with rapid accumulation of inducible
NO synthase (iNOS) protein and the production of nitrite. The
uncontrolled growth of BCG-vector was associated with low iNOS
expression but no nitrite production. Thus, iNOS expression appears to
be TNF- independent but iNOS generation of NO requires TNF-. In
cultures of TNF-KO macrophages infected with BCG-TNF, inhibition of
iNOS by aminoguanidine (AMG) abolished the killing of the bacilli.
However, the growth of the organisms was still inhibited, suggesting an
iNOS-independent TNF--mediated growth inhibition. To confirm this,
macrophages from iNOS-KO mice were infected with either BCG-vector or
BCG-TNF. As expected, no nitrite was detected in the culture medium.
TNF- was detected only when the cells were infected with BCG-TNF. In
the iNOS-KO macrophages, the growth of BCG was inhibited only in the
BCG-TNF infection. These results suggest that in the absence of iNOS
activity, TNF- stimulates macrophages to control the growth of
intracellular BCG. Thus, there appears to be both a
TNF--dependent-iNOS-dependent killing pathway as well as a
TNF--dependent-iNOS-independent growth inhibitory pathway for the
control of intracellular mycobacteria in murine
macrophages.
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