title: Histamine plays an essential regulatory role in lung inflammation and protective immunity in the acute phase of Mycobacterium tuberculosis infection.
abstract: 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.
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: D
authors.initials: D
authors.lastname: Carlos
authors.forename: C
authors.initials: C
authors.lastname: Fremond
authors.forename: A
authors.initials: A
authors.lastname: Samarina
authors.forename: V
authors.initials: V
authors.lastname: Vasseur
authors.forename: I
authors.initials: I
authors.lastname: Maillet
authors.forename: S G
authors.initials: SG
authors.lastname: Ramos
authors.forename: F
authors.initials: F
authors.lastname: Erard
authors.forename: V
authors.initials: V
authors.lastname: Quesniaux
authors.forename: H
authors.initials: H
authors.lastname: Ohtsu
authors.forename: C L
authors.initials: CL
authors.lastname: Silva
authors.forename: L H
authors.initials: LH
authors.lastname: Faccioli
authors.forename: B
authors.initials: B
authors.lastname: Ryffel
mesh_terms: 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*
chemical_list: D016207:Cytokines; D009569:Nitric Oxide; D006632:Histamine; D006640:Histidine Decarboxylase