Mast cells play a key role in the development of late airway hyperresponsiveness through TNF-alpha in a murine model of asthma.
We have investigated the role of TNF-alpha in mast cell-mediated late airway hyperresponsiveness (AHR) using mast cell-deficient WBB6F1-W/W(v) (W/W(v)) mice in a murine model of asthma, which exhibits a biphasic increase in AHR. TNF-alpha levels in the airway and magnitude of late AHR in response to airway allergen challenge were severely impaired in W/W(v) mice compared to their littermates. In addition to TNF-alpha, cytosolic phospholipase A(2) (cPLA(2)) phosphorylation and enzymatic activity in the lungs were also impaired in W/W(v) mice. Either anti-TNF-alpha antibody or an inhibitor of cPLA(2) abolished late AHR in congeneic +/+ mice. Intratracheal administration of TNF-alpha resulted in increases in late AHR, cPLA(2 )phosphorylation, cPLA(2 )activity, and phosphorylation of mitogen-activated protein kinases. Mast cell replacement restored airway TNF-alpha level, cPLA(2 )phosphorylation and enzymatic activity in the lungs as well as late AHR in W/W(v) mice. These data indicate that mast cells play a key role in the development of late AHR through liberation of TNF-alpha.
Kim
Young-Suk
YS
Department of Immunology, Chonbuk National University Medical School, Chonju, Republic of Korea.
Ko
Hyun-Mi
HM
Kang
Nam-In
NI
Song
Chang-Ho
CH
Zhang
Xin
X
Chung
Woo-Chan
WC
Kim
Jae-Hong
JH
Choi
In-Hak
IH
Park
Young-Min
YM
Kim
Gi-Young
GY
Im
Shun-Young
SY
Lee
Hern-Ku
HK
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D014409:Tumor Necrosis Factor-alpha