The Failure of STAT6-deficient Mice to Develop Airway Eosinophilia and Airway Hyperresponsiveness Is Overcome by Interleukin-5

Tomkinson, Adrian; Kanehiro, Arihiko; Rabinovitch, Nathan; Joetham, Anthony; Cieslewicz, Grzegorz; Gelfand, Erwin W.

doi:10.1164/ajrccm.160.4.9809065

Cited by 118 publications

(107 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This suggests that eosinophilia and AHR are independent of each other in this model. Several studies have also observed dissociation between eosinophilia and AHR in mice following allergen sensitization and challenge (10,14,16,40,41).…”

Section: Discussionmentioning

confidence: 98%

Allergen-induced airway disease is mouse strain dependent

Whitehead

Walker

Berman

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

169

119

View full text Add to dashboard Cite

We investigated the development of airway hyperreactivity (AHR) and inflammation in the lungs of nine genetically diverse inbred strains of mice [129/SvIm, A/J, BALB/cJ, BTBR+(T)/tf/tf, CAST/Ei, C3H/HeJ, C57BL/6J, DBA/2J, and FVB/NJ] after sensitization and challenge with ovalbumin (OVA). At 24, 48, and 72 h post-OVA exposure, the severity of AHR and eosinophilic inflammation of the mouse strains ranged from relatively unresponsive to responsive. The severity of the airway eosinophilia of some strains did not clearly correlate with the development of AHR. The temporal presence of T helper type 2 cytokines in lung lavage fluid also varied markedly among the strains. The levels of IL-4 and IL-13 were generally increased in the strains with the highest airway eosinophilia at 24 and 72 h postexposure, respectively; the levels of IL-5 were significantly increased in most of the strains with airway inflammation over the 72-h time period. The differences of physiological and biological responses among the inbred mouse strains after OVA sensitization and challenge support the hypothesis that genetic factors contribute, in part, to the development of allergen-induced airway disease.

show abstract

Section: Discussionmentioning

confidence: 98%

Allergen-induced airway disease is mouse strain dependent

Whitehead

Walker

Berman

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

169

119

View full text Add to dashboard Cite

show abstract

“…In mouse models of allergic lung inflammation (41)(42)(43), contact hypersensitivity (44), and allergic diarrhea (45), STAT6 deficiency was accompanied by a lack of eosinophil influx into the sites of allergic inflammation. This effect may be at least partially due to defective eotaxin-1 production in these animals.…”

Section: Discussionmentioning

confidence: 99%

STAT6 Mediates Eotaxin-1 Expression in IL-4 or TNF-α-Induced Fibroblasts

Hoeck

Woisetschläger

2001

The Journal of Immunology

127

137

View full text Add to dashboard Cite

Eosinophils are attracted to sites of allergic inflammation by a number of chemoattractants including eotaxin-1. This chemokine can be secreted from epithelial cells and fibroblasts after IL-4 and TNF-α stimulation in a synergistic fashion. TNF-α activated gene expression at the transcriptional level in a STAT6-dependent manner, because: 1) eotaxin-1 promoter luciferase constructs were TNF-α inducible in STAT6-defective HEK293 cells only on cotransfection of STAT6 expression vector, an effect that was partially mediated by activation-induced binding of NF-κB proteins to a composite STAT6/NF-κB element; 2) reporter constructs defective in STAT6 DNA binding did not respond to TNF-α stimulation; 3) eotaxin-1 protein secretion was detected only in STAT6-transfected HEK293 cell supernatants on TNF-α treatment; and 4) a trans-dominant negative STAT6 protein inhibited TNF-α-induced eotaxin-1 secretion in primary fibroblasts. TNF-α inducibility of the IL-8 and monocyte chemoattractant protein-1 genes was not dependent on STAT6 expression in the same experimental systems. The inducing effect of IL-4 and IL-13 was also mediated by STAT6. The synergistic effect of IL-4 and TNF-α observed at the RNA and the protein level was not seen at the promoter level. The data demonstrate that both IL-4 and TNF-α induce eotaxin-1 expression at the level of transcription via a STAT6-mediated pathway.

show abstract

“…Consistent with defective induction of type 2 responses, we found a striking reduction in the expression of Th2-dependent airway inflammatory responses. The reduced airway inflammation in p110d-inactivated mice is most likely to result from defective induction of type 2 responses, since type 2 cytokines such as IL-4, IL-5 and IL-13 are known to play critical roles in the induction of airway eosinophila [20][21][22][23]. Notably, reduced Th2 airway inflammation had significant effects on lung function, as p110d-inactivated mice were resistant to the development of methacholine-induced respiratory hyperresponsiveness after allergen challenge.…”

mentioning

confidence: 99%

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

et al. 2007

View full text Add to dashboard Cite

Phosphoinositide 3-kinases (PI3K) regulate immune activation via their roles in signal transduction of multiple classes of receptors. Here, we examined the effect of genetic inactivation of the hemopoietic cell-restricted PI3K isoform p110d on systemic cytokine and chemokine responses and allergic airway inflammation. We found that type 2 cytokine responses (IL-4, IL-5 and IL-13) are significantly decreased in p110d mutants, whereas type 1 cytokine responses (IFN-c and CXCL10) were robust. Elevated IFN-c production during the primary response to ovalbumin (OVA) was associated with reduced production of the regulatory cytokine IL-10. IFN-c and IL-10 production normalized after secondary OVA immunization; however, type 2 cytokine production was persistently reduced. Type 2 cytokine-dependent airway inflammation elicited by intranasal challenge with OVA was dramatically reduced, with reduced levels of eosinophil recruitment and mucus production observed in the lungs. Induction of respiratory hyper-responsiveness to inhaled methacholine, a hallmark of asthma, was markedly attenuated in p110d-inactivated mice. Adoptive transfer of OVA-primed splenocytes from normal but not p110d-inactivated mice could induce airway eosinophilia in naive, airway-challenged recipient mice. These data demonstrate a novel functional role for p110d signaling in induction of type 2 responses in vivo and may offer a new therapeutic target for Th2-mediated airway disease. IntroductionPhosphoinositide 3-kinases (PI3K) are key signaling enzymes regulating immune function [1,2]. PI3K are activated by stimulation through a variety of receptor types, including antigen receptors, costimulatory receptors and certain cytokine receptors. PI3K function by phosphorylating specific plasma membrane phospholipids to generate short-lived, membrane-integral lipid [3,4]. Effects of regulatory subunit deficiencies on T cells are less clear: deficiency of the p85a regulatory subunit for class 1A PI3K was reported to have no effect on T cell activation in vitro, while deficiency in the p85b regulatory subunit increased T cell proliferation in vitro [5]. One group found that p85-deficient mice have enhanced responses to Leishmania infection [6], but reduced immunity to nematode infection [7], suggesting that impaired class IA PI3K signaling leads to an immune dysregulation rather than a general immunodeficiency. However, the interpretation of these studies is complicated because regulatory subunits each affect the stability and activity of multiple catalytic subunits and may have adaptor functions in signaling independent of PI3K catalytic subunits.Recent work has begun to explore the specific roles of different PI3K catalytic subunit isoforms in immune function. Analysis of p110a and p110b deficiency has been hindered by the lethality of these mutations [8,9]. Mice deficient in the class IB subunit p110c are viable and have defects in T cell development and activation, as well as severe defects in neutrophil function, while B cell activation appears normal [1...

show abstract

The Failure of STAT6-deficient Mice to Develop Airway Eosinophilia and Airway Hyperresponsiveness Is Overcome by Interleukin-5

Cited by 118 publications

References 34 publications

Allergen-induced airway disease is mouse strain dependent

Allergen-induced airway disease is mouse strain dependent

STAT6 Mediates Eotaxin-1 Expression in IL-4 or TNF-α-Induced Fibroblasts

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

Contact Info

Product

Resources

About