IL-10 gene knockout attenuates allergen-induced airway hyperresponsiveness in C57BL/6 mice.
Intratracheal administration of interleukin-10 (IL-10) has been reported to inhibit allergic inflammation but augment airway hyperresponsiveness (AHR). In the present study, airway and smooth muscle responsiveness to methacholine (MCh) were compared in wild-type (WT) and IL-10-deficient (IL-10-KO) mice to investigate the role of endogenous IL-10 in AHR development. Naive WT and IL-10-KO mice exhibited similar dose-dependent increases in airway resistance (Raw) to intravenous MCh. Sensitization and challenge with ragweed (RW) induced a twofold increase in responsiveness to intravenous MCh in WT mice, but hyperresponsiveness was not observed in similarly treated IL-10-KO mice. Likewise, tracheal rings from RW-sensitized and -challenged WT mice exhibited a fourfold greater responsiveness to MCh than IL-10-KO tracheal preparations. Measurements of airway constriction by whole body plethysmography further supported the Raw and tracheal ring data (i.e., AHR was not observed in the absence of IL-10). Interestingly, factors previously implicated in the development of AHR, including IL-4, IL-5, IL-13, IgA, IgG1, IgE, eosinophilia, and lymphocyte recruitment to the airways, were upregulated in the IL-10-KO mice. Treatment with recombinant murine IL-10 at the time of allergen challenge reduced the magnitude of inflammation but reinstated AHR development in IL-10-KO mice. Adoptive transfer of mononuclear splenocytes to IL-10-sufficient severe combined immunodeficient mice indicated that lymphocytes were an important source of the IL-10 impacting AHR development. These results provide evidence that IL-10 expression promotes the development of allergen-induced smooth muscle hyperresponsiveness.
Justice
J P
JP
Departments of Physiology and Pharmacology, Brody School of Medicine at East Carolina University, Greenville, North Carolina 27858, USA.
Shibata
Y
Y
Sur
S
S
Mustafa
J
J
Fan
M
M
Van Scott
M R
MR
D019264:Adoptive Transfer; D000485:Allergens / Q000276:immunology*; D000818:Animals; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D007136:Immunoglobulins / Q000097:blood; D066298:In Vitro Techniques; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000008:administration & dosage / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*; D018793:Interleukin-13 / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D015848:Interleukin-5 / Q000032:analysis; D008297:Male; D016210:Methacholine Chloride; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D018418:Th2 Cells / Q000276:immunology
D000485:Allergens; D007136:Immunoglobulins; D018793:Interleukin-13; D015848:Interleukin-5; D011994:Recombinant Proteins; D016210:Methacholine Chloride; D016753:Interleukin-10; D015847:Interleukin-4