Interleukin-13 (IL-13)/IL-13 Receptor α1 (IL-13Rα1) Signaling Regulates Intestinal Epithelial Cystic Fibrosis Transmembrane Conductance Regulator Channel-dependent Cl− Secretion

Wu, David; Ahrens, Richard; Osterfeld, Heather; Noah, Taeko K.; Groschwitz, Katherine; Foster, Paul S.; Steinbrecher, Kris A.; Rothenberg, Marc E.; Shroyer, Noah F.; Matthaei, Klaus I.; Finkelman, Fred D.; Hogan, Simon P.

doi:10.1074/jbc.m110.214965

Cited by 51 publications

(38 citation statements)

References 72 publications

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“…Puromycin-resistant cells were passaged for 14 days and demonstrated stable green fluorescent protein gene expression (results not shown). The lentiviraltransduced Caco-2 BBe cells (passages 1-5) were grown to confluency under puromycin selection pressure until they reached Ͼ250 ⍀·cm 2 ; electrophysiological and biochemical analyses were performed as described elsewhere (82). PAR-2 knockdown was confirmed by Western blot analysis using the anti-PAR-2 MAb (Santa Cruz Biotechnology).…”

Section: Methodsmentioning

confidence: 99%

“…For lentiviral short-hairpin RNA (shRNA) transduction, Caco-2 BBe cells at 70 -90% confluence were transduced with lentiviral particles containing shRNAs targeting PAR-2 (PAR-2 shRNA lentiviral particles; catalog no. sc-36188-v, Santa Cruz Biotechnology) or a nontarget control shRNA (82). Lentiviral particles were incubated with Caco-2 BBe cells (multiplicity of infection ϳ10) in the presence of Polybrene (4 g/ml; Sigma) for 24 h and then selected in puromycin at a concentration that killed uninfected cells within 3 days (2 g/ml).…”

Section: Methodsmentioning

confidence: 99%

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Chymase-mediated intestinal epithelial permeability is regulated by a protease-activating receptor/matrix metalloproteinase-2-dependent mechanism

Groschwitz

Osterfeld

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Chymase-mediated intestinal epithelial permeability is regulated by a protease-activating receptor/matrix metalloproteinase-2-dependent mechanism

Groschwitz

Osterfeld

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…C57BL/6J cells were treated as described 24 h apart, and tissues were harvested 24 h later. Terminal ileum was harvested and assessed using a Ussing chamber as previously described (57). …”

Section: Methodsmentioning

confidence: 99%

Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases

McNally

Millen

Chaturvedi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Antigen-activated lymphocytes undergo extraordinarily rapid cell division in the course of immune responses. We hypothesized that this unique aspect of lymphocyte biology leads to unusual genomic stress in recently antigen-activated lymphocytes and that targeted manipulation of DNA damage-response (DDR) signaling pathways would allow for selective therapeutic targeting of pathological T cells in disease contexts. Consistent with these hypotheses, we found that activated mouse and human T cells display a pronounced DDR in vitro and in vivo. Upon screening a variety of small-molecule compounds, we found that potentiation of p53 (via inhibition of MDM2) or impairment of cell cycle checkpoints (via inhibition of CHK1/2 or WEE1) led to the selective elimination of activated, pathological T cells in vivo. The combination of these strategies [which we termed "p53 potentiation with checkpoint abrogation" (PPCA)] displayed therapeutic benefits in preclinical disease models of hemophagocytic lymphohistiocytosis and multiple sclerosis, which are driven by foreign antigens or self-antigens, respectively. PPCA therapy targeted pathological T cells but did not compromise naive, regulatory, or quiescent memory T-cell pools, and had a modest nonimmune toxicity profile. Thus, PPCA is a therapeutic modality for selective, antigen-specific immune modulation with significant translational potential for diverse immune-mediated diseases.autoimmunity | immune regulation | DNA damage response | therapeutics T he immune system has evolved under intense pressure from pathogens that proliferate very rapidly (1). In responding to infections, the adaptive immune system needs to mobilize rare pathogen-specific lymphocytes quickly. This mobilization is achieved by rapid, exponential expansion of responding lymphocyte clones. Indeed, antigen-activated T and B cells appear to have some of the most rapid division rates among all mammalian cell types (2). We hypothesized that this unique aspect of lymphocyte biology would cause significant genomic stress in responding lymphocytes and that novel forms of therapeutic immune suppression could be developed by exploiting this weakness. Such strategies would allow for "developmental" or "kinetic" targeting of pathological immune responses at the time of disease activity or organ rejection and could complement or replace chronic suppression of immune signaling or cytokine pathways. The recent preclinical and clinical development of a wide array of rationally designed small-molecule inhibitors of various signaling and effector molecules within DNA damage-response (DDR) cascades has provided an opportunity to test this hypothesis (3, 4).We first looked for evidence of a DDR occurring in activated T cells in physiological contexts and found a broad DDR in murine and human T cells. Next, upon screening an array of DNA-damaging agents and DDR-altering small molecules for their ability to kill activated, but not resting, T cells, we identified two promising strategies. We found that inhibition of MDM2 (an end...

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“…IL-13 acts in mucosal immunity as a factor that stimulates goblet cells to produce mucus, attracts eosinophils by local eotaxin to release and increase the IgE production. In addition, IL-13 has a possible contribution to increase gut motility and epithelial secretion [137,138].…”

Section: Il-13 In Gastrointestinal Infl Ammatory Diseasesmentioning

confidence: 99%

Interleukin-13 as an important cytokine: A review on its roles in some human diseases

Seyfizadeh

Gharibi

Babaloo

2015

Acta Microbiologica et Immunologica Hungarica

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Interleukin-13 (IL-13) as a pleiotropic cytokine acts through the IL-13Ra1/ IL-4Ra complex to induce activation responses which contribute to the infl ammatory diseases. Genetic polymorphisms in IL-13 and its receptor components have been proved to be associated with higher disease prevalence rates. Animal models such as in IL-13 defi cient mice and transgenic animals also have been confi rmed the critical role of this cytokine in the immune responses, mostly by IL-13 neutralization and IL-13/IL-4 dual neutralization strategies. This review highlights IL-13 structure as well as its pivotal roles in the normal physiologic and pathologic states. It is followed by a section on the recent fi ndings on IL-13 receptors and signalling mechanisms to briefl y summarize its functions in the immune systems. IL-13 roles in the human diseases such as asthma, systematic sclerosis, and some infl ammatory diseases are described concisely. Finally some of the ongoing therapeutic applications are presented to comprehensively review IL-13 mediator roles.

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Interleukin-13 (IL-13)/IL-13 Receptor α1 (IL-13Rα1) Signaling Regulates Intestinal Epithelial Cystic Fibrosis Transmembrane Conductance Regulator Channel-dependent Cl− Secretion

Cited by 51 publications

References 72 publications

Chymase-mediated intestinal epithelial permeability is regulated by a protease-activating receptor/matrix metalloproteinase-2-dependent mechanism

Chymase-mediated intestinal epithelial permeability is regulated by a protease-activating receptor/matrix metalloproteinase-2-dependent mechanism

Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases

Interleukin-13 as an important cytokine: A review on its roles in some human diseases

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