Bryce Paul J, Mathias Clinton B, Harrison Krista L, Watanabe Takeshi, Geha Raif S, Oettgen Hans C
Division of Immunology, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
J Clin Invest. 2006 Jun;116(6):1624-32. doi: 10.1172/JCI26150. Epub 2006 May 4.
Histamine, signaling via the type 1 receptor (H1R), has been shown to suppress Th2 cytokine production by in vitro cultured T cells. We examined the role of H1R in allergic inflammation in vivo using a murine asthma model. Allergen-stimulated splenic T cells from sensitized H1R-/- mice exhibited enhanced Th2 cytokine production. Despite this Th2 bias, allergen-challenged H1R-/- mice exhibited diminished lung Th2 cytokine mRNA levels, airway inflammation, goblet cell metaplasia, and airway hyperresponsiveness (AHR). Restoration of pulmonary Th2 cytokines in H1R-/- mice by intranasal IL-4 or IL-13 restored inflammatory lung responses and AHR. Further investigation revealed that histamine acts as a T cell chemotactic factor and defective T cell trafficking was responsible for the absence of lung inflammation. Cultured T cells migrated in response to histamine in vitro, but this was ablated by blockade of H1R but not H2R. In vivo, allergen-specific WT but not H1R-/- CD4+ T cells were recruited to the lungs of naive recipients following inhaled allergen challenge. H1R-/- T cells failed to confer airway inflammation or AHR observed after transfer of WT T cells. Our data establish a role for histamine and H1R in promoting the migration of Th2 cells into sites of allergen exposure.
组胺通过1型受体（H1R）发出信号，已被证明可抑制体外培养的T细胞产生Th2细胞因子。我们使用小鼠哮喘模型研究了H1R在体内过敏性炎症中的作用。来自致敏的H1R基因敲除小鼠的变应原刺激的脾T细胞表现出增强的Th2细胞因子产生。尽管存在这种Th2偏向，但变应原激发的H1R基因敲除小鼠的肺Th2细胞因子mRNA水平、气道炎症、杯状细胞化生和气道高反应性（AHR）均降低。通过鼻内给予IL-4或IL-13恢复H1R基因敲除小鼠肺部的Th2细胞因子可恢复炎症性肺反应和AHR。进一步研究表明，组胺作为一种T细胞趋化因子，T细胞转运缺陷是肺部炎症缺失的原因。体外培养的T细胞对组胺有反应而迁移，但H1R而非H2R的阻断可消除这种迁移。在体内，吸入变应原激发后，变应原特异性野生型而非H1R基因敲除的CD4 + T细胞被募集到未致敏受体的肺部。H1R基因敲除的T细胞在转移野生型T细胞后未能引发观察到的气道炎症或AHR。我们的数据证实了组胺和H1R在促进Th2细胞迁移到变应原暴露部位中的作用。
