Histamine plays an essential regulatory role in lung inflammation and protective immunity in the acute phase of Mycobacterium tuberculosis infection.
The course and outcome of infection with mycobacteria are determined by a complex interplay between the immune system of the host and the survival mechanisms developed by the bacilli. Recent data suggest a regulatory role of histamine not only in the innate but also in the adaptive immune response. We used a model of pulmonary Mycobacterium tuberculosis infection in histamine-deficient mice lacking histidine decarboxylase (HDC(-/-)), the histamine-synthesizing enzyme. To confirm that mycobacterial infection induced histamine production, we exposed mice to M. tuberculosis and compared responses in C57BL/6 (wild-type) and HDC(-/-) mice. Histamine levels increased around fivefold above baseline in infected C57BL/6 mice at day 28 of infection, whereas only small amounts were detected in the lungs of infected HDC(-/-) mice. Blocking histamine production decreased both neutrophil influx into lung tissue and the release of proinflammatory mediators, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), in the acute phase of infection. However, the accumulation and activation of CD4(+) T cells were augmented in the lungs of infected HDC(-/-) mice and correlated with a distinct granuloma formation that contained abundant lymphocytic infiltration and reduced numbers of mycobacteria 28 days after infection. Furthermore, the production of IL-12, gamma interferon, and nitric oxide, as well as CD11c(+) cell influx into the lungs of infected HDC(-/-) mice, was increased. These findings indicate that histamine produced after M. tuberculosis infection may play a regulatory role not only by enhancing the pulmonary neutrophilia and production of IL-6 and TNF-alpha but also by impairing the protective Th1 response, which ultimately restricts mycobacterial growth.
Carlos
D
D
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
Fremond
C
C
Samarina
A
A
Vasseur
V
V
Maillet
I
I
Ramos
S G
SG
Erard
F
F
Quesniaux
V
V
Ohtsu
H
H
Silva
C L
CL
Faccioli
L H
LH
Ryffel
B
B
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D006099:Granuloma / Q000382:microbiology / Q000473:pathology; D006632:Histamine / Q000276:immunology*; D006640:Histidine Decarboxylase / Q000172:deficiency; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000473:pathology*
D016207:Cytokines; D009569:Nitric Oxide; D006632:Histamine; D006640:Histidine Decarboxylase