Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 120, Issue 1, Pages 48-55Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2007.02.046
Keywords
airway hyperreactivity; asthma; cytokines; mast cells; TNF
Categories
Funding
- NCI NIH HHS [CA72074, R01 CA072074] Funding Source: Medline
- NHLBI NIH HHS [P50 HL067674, HL67674] Funding Source: Medline
- NIAID NIH HHS [R01 AI023990, AI23990, R01 AI070813, AI070813] Funding Source: Medline
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Background: Mast cells, IgE, and TNF, which have been implicated in human atopic asthma, contribute significantly to the allergic airway inflammation induced by ovalbumin (OVA) challenge in mice sensitized with OVA without alum. However, it is not clear to what extent mast cells represent a significant source of TNF in this mouse model. Objective: We investigated the importance of mast cell-derived TNF in a mast cell-dependent model of OVA-induced airway hyperreactivity (AHR) and allergic airway inflammation. Methods: Features of this model of airway inflammation were analyzed in C57BL/6J-wild-type mice, mast cell-deficient C57BL/6J-Kit(W-sh/W-sh) mice, and C57BL/6J Kit(W-sh/W-sh) mice that had been systemically engrafted with bone marrow-derived cultured mast cells from C57BL/6J-wild-type or C57BL/6J-TNF-/- mice. Results: Ovalbumin-induced AHR and airway inflammation were significantly reduced in mast cell-deficient Kit(W-sh/W-sh) mice versus wild-type mice. By contrast, Kit(W-sh/W-sh) mice that had been engrafted with wild-type but not with TNF-/- bone marrow-derived cultured mast cells exhibited responses very similar to those observed in wild-type mice. Mast cells and mast cell-derived TNF were not required for induction of OVA-specific memory T cells in the sensitization phase, but significantly enhanced lymphocyte recruitment and T(H)2 cytokine production in the challenge phase. Conclusion: Mast cell-derived TNF contributes significantly to the pathogenesis of mast cell-dependent and IgE-dependent, OVA-induced allergic inflammation and AHR in mice, perhaps in part by enhancing lymphocyte recruitment and T(H)2 cytokine production. Clinical implications: Our findings in mice support the hypothesis that mast cell-derived TNF can promote allergic inflammation and AHR in asthma.
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