Complex Role of the IL-4 Receptor α in a Murine Model of Airway Inflammation: Expression of the IL-4 Receptor α on Nonlymphoid Cells of Bone Marrow Origin Contributes to Severity of Inflammation

Kelly-Welch, Ann E.; Melo, Marco; Smith, E. L.; Ford, Andrew; Haudenschild, Christian C.; Noben-Trauth, Nancy; Keegan, Achsah

doi:10.4049/jimmunol.172.7.4545

Cited by 63 publications

(81 citation statements)

References 57 publications

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“…In the absence of IL-4R alpha in recipient mice, there was no goblet cell metaplasia or mucus hypersecretion in response to OVA, even in the presence of Th2 cells and substantial eosinophilic infiltration [23] . It was reported that the expression of Th2 cytokines was unaffected as a consequence of the CCR3-mediated depletion of eosinophils in OVA-sensitized/challenged mice [26] . However, CCR3-mediated signaling can rapidly mobilize IL-4 stored in human eosinophils for release by vesicular transport to contribute to immune responses [27] .…”

Section: Discussionmentioning

confidence: 99%

Human C-C chemokine receptor 3 monoclonal antibody inhibits pulmonary inflammation in allergic mice1

Wang

Shen

et al. 2007

Acta Pharmacol Sin

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Aim: To evaluate the effect of C-C chemokine receptor 3 (CCR3) blockade on pulmonary inflammation and mucus production in allergic mice. Methods: We used the synthetic peptide of the CCR3 NH2-terminal as the immunizing antigen and generated murine monoclonal antibody against the human CCR3. In addition, the generated antibody was administered to mice sensitized and challenged with ovalbumin. The inflammatory cells in bronchoalveolar lavage, cytokine levels, pulmonary histopathology, and mucus secretion were examined. Results: The Western blotting analysis indicated that the generated antibody bound to CCR3 specifically. The allergic mice treated with the antihuman CCR3 antibody exhibited a significant reduction of pulmonary inflammation accompanied with the alteration of cytokine. Conclusion: The antibody we generated was specific to CCR3. The inhibition of airway inflammation and mucus overproduction by the antibody suggested that the blockade of CCR3 is an appealing therapeutical target for asthma. The present research may provide an experimental basis for the further study of this agent.

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Section: Discussionmentioning

confidence: 99%

Human C-C chemokine receptor 3 monoclonal antibody inhibits pulmonary inflammation in allergic mice1

Wang

Shen

et al. 2007

Acta Pharmacol Sin

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“…IL-4 and IL-13 have distinct biological functions, with IL-4 being involved in amplifying the Th2 inflammatory axis through the priming of Th2 cells, whereas IL-13 triggers physiological changes leading to airway hyper-reactivity, mucus hypersecretion, and lung remodeling (59). In humans and mouse models of allergic asthma, M2 macrophages are associated with the severity of allergic asthma and decreased lung function (12,13). In this study, we aimed to define the regulatory mechanisms acting on IL-4 signaling and M2 development.…”

Section: Discussionmentioning

confidence: 99%

Suppressor of Cytokine Signaling (SOCS)1 Regulates Interleukin-4 (IL-4)-activated Insulin Receptor Substrate (IRS)-2 Tyrosine Phosphorylation in Monocytes and Macrophages via the Proteasome

McCormick¹,

Gowda²,

Fang³

et al. 2016

Journal of Biological Chemistry

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Allergic asthma is a chronic lung disease initiated and driven by Th2 cytokines IL-4/-13. In macrophages, IL-4/-13 bind IL-4 receptors, which signal through insulin receptor substrate (IRS)-2, inducing M2 macrophage differentiation. M2 macrophages correlate with disease severity and poor lung function, although the mechanisms that regulate M2 polarization are not understood. Following IL-4 exposure, suppressor of cytokine signaling (SOCS)1 is highly induced in human monocytes. We found that siRNA knockdown of SOCS1 prolonged IRS-2 tyrosine phosphorylation and enhanced M2 differentiation, although siRNA knockdown of SOCS3 did not affect either. By co-immunoprecipitation, we found that SOCS1 complexes with IRS-2 at baseline, and this association increased after IL-4 stimulation. Because SOCS1 is an E3 ubiquitin ligase, we examined the effect of proteasome inhibitors on IL-4-induced IRS-2 phosphorylation. Proteasomal inhibition prolonged IRS-2 tyrosine phosphorylation, increased ubiquitination of IRS-2, and enhanced M2 gene expression. siRNA knockdown of SOCS1 inhibited ubiquitin accumulation on IRS-2, although siRNA knockdown of SOCS3 had no effect on ubiquitination of IRS-2. Monocytes from healthy and allergic individuals revealed that SOCS1 is induced by IL-4 in healthy monocytes but not allergic cells, whereas SOCS3 is highly induced in allergic monocytes. Healthy monocytes displayed greater ubiquitination of IRS-2 and lower M2 polarization than allergic monocytes in response to IL-4 stimulation. Here, we identify SOCS1 as a key negative regulator of IL-4-induced IRS-2 signaling and M2 differentiation. Our findings provide novel insight into how dysregulated expression of SOCS increases IL-4 responses in allergic monocytes, and this may represent a new therapeutic avenue for managing allergic disease.Allergic asthma is an immune disorder characterized by elevation of total and specific IgE and infiltration of monocytes, lymphocytes, mast cells, eosinophils, and basophils in the lungs that causes inflammation and wheezing, cough, and dyspnea (1-4). A complex interplay of genetic and environmental factors contributes to the onset and maintenance of these diseases. Mechanistically, it is known that cytokines secreted from Th2 cells, such as interleukin (IL)-4, IL-5, IL-9, and IL-13, have a pivotal role in dictating the pathology of allergic disease (1, 2, 5, 6). The pathways by which IL-4 and IL-13 exert their biological effects have been a major focus of research and development of therapeutics to block their action through type I and II IL-4 receptors. Previously, we showed that in macrophages, IL-4 engagement of the type I IL-4 receptor resulted in robust tyrosine phosphorylation of insulin receptor substrate (IRS)-2, recruitment of p85 regulatory subunit of PI3K and GRB2, and strong induction of a subset of hallmark M2, also known as M(IL-4) (7), macrophage genes (8, 9). In contrast, IL-13 binding to the type II receptor resulted in only modest IRS-2 phosphorylation. Increasing the concentration of IL-13 did n...

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“…28,29 Briefly, wild-type mice were immunized with aluminium hydroxide alone or 100 lg OVA/alumimium hydroxide by intraperitoneal injection on day 1 and boosted with the same reagents on day 6. Mice were then exposed to 1% OVA in PBS by nebulization for 20 min each day on days 12 and 14.…”

Section: Ovalbumin Model Of Asthmamentioning

confidence: 99%

Splice isoforms of human interleukin-4 are functionally active in mice in vivo

et al. 2011

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Summary Interleukin‐4 (IL‐4) acts on cultured cells in a species‐specific fashion, although several reports have suggested that human (h) IL‐4 may be functionally active in rodents in vivo. The latter finding, if true, would not only offer possibilities for pre‐clinical testing of novel hIL‐4‐targeting therapies in animals, but also suggests new opportunities for mechanistic studies of IL‐4 and its receptors. Conventional IL‐4 is encoded by four exons, whereas its poorly studied alternatively spliced isoform is encoded by exons 1, 3 and 4 (IL‐4δ2). Replication‐deficient adenovirus‐mediated gene delivery of hIL‐4 isoforms (hIL‐4 or hIL‐4δ2) to mouse lungs caused similar pulmonary infiltration of T and B lymphocytes, but not eosinophils. There were significant differences in the changes of pulmonary cytokine milieu induced by hIL‐4 compared with hIL‐4δ2, with hIL‐4δ2 inducing higher levels of pro‐inflammatory (tumour necrosis factor‐α, IL‐1, and monocyte chemotactic protein‐1) and T helper type 1 (IL‐12 and interferon‐γ) cytokines. There was no elevation in endogenous mouse (m) IL‐4 or mIL‐4δ2 mRNAs, and germ‐line deficiency of mIL‐4 did not affect the degree of pulmonary infiltration. When combined with an ovalbumin model of asthma, hIL‐4δ2 stimulated a greater accumulation of lymphocytes than did hIL‐4. Pulmonary infiltration of lymphocytes induced by expression of hIL‐4 or hIL‐4δ2 was attenuated, but not completely abrogated, by germ‐line deficiency of mIL‐4Rα or murine signal transducer and activator of transcription 6, suggesting that these signalling molecules mediate the in vivo effects of hIL‐4 isoforms in mice. These findings suggest that splice isoforms of human IL‐4 are functionally active in vivo in mice, and partially share the effects of the corresponding species‐specific isoforms.

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Complex Role of the IL-4 Receptor α in a Murine Model of Airway Inflammation: Expression of the IL-4 Receptor α on Nonlymphoid Cells of Bone Marrow Origin Contributes to Severity of Inflammation

Cited by 63 publications

References 57 publications

Human C-C chemokine receptor 3 monoclonal antibody inhibits pulmonary inflammation in allergic mice1

Human C-C chemokine receptor 3 monoclonal antibody inhibits pulmonary inflammation in allergic mice1

Suppressor of Cytokine Signaling (SOCS)1 Regulates Interleukin-4 (IL-4)-activated Insulin Receptor Substrate (IRS)-2 Tyrosine Phosphorylation in Monocytes and Macrophages via the Proteasome

Splice isoforms of human interleukin-4 are functionally active in mice in vivo

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