IL-13 downregulates PPAR-γ/heme oxygenase-1 via ER stress-stimulated calpain activation: aggravation of activated microglia death

Liu, Shing‐Hwa; Yang, Cheng; Pan, Hung Chuan; Sung, Yen Jen; Liao, Ko Kaung; Chen, Wen Bao; Lin, Wen Zheng; Sheu, Meei-Ling

doi:10.1007/s00018-009-0255-4

Cited by 36 publications

(50 citation statements)

References 57 publications

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“…Sequestration of iron into ferritin and its recycling in the tissues is part of a homeodynamic process that controls oxidation-reduction in cellular metabolism. We confirmed (Liu et al, 2010) that LPSinduced Hmox1 expression is reduced by IL-13 (Supplemental Fig. 1A), and we also found that LPS-increased Hmox1 activity was reduced by IL-13, determined by measuring bilirubin production (Supplemental Fig.…”

Section: Ep2 Promotes Microglia Deathsupporting

confidence: 85%

“…IL-13 promotes the death of LPSactivated microglia characterized by positive terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling staining and DNA fragmentation (Yang et al, 2002), together with caspase-12-mediated endoplasmic reticulum stress (Szegezdi et al, 2003;Liu et al, 2010), suggesting an apoptotic mode of microglial death. We found that microglial death induced by LPS/IL-13 was blocked by two caspase-1 inhibitors (Fig.…”

Section: Ep2 Promotes Microglia Deathmentioning

confidence: 99%

“…IL-13 is a canonical type 2 cytokine produced by many cell types that induces a state of alternative activation in macrophages and microglia (Van Dyken and Locksley, 2013). In classically activated microglia, IL-13 also opposes the induction of a major antioxidant protein, heme oxygenase 1 (Hmox1), and the resulting oxidative stress might contribute to development of the apoptotic state of microglia (Liu et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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EP2 Receptor Signaling Regulates Microglia Death

Yang

Jiang

et al. 2015

Mol Pharmacol

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The timely resolution of inflammation prevents continued tissue damage after an initial insult. In the brain, the death of activated microglia by apoptosis has been proposed as one mechanism to resolve brain inflammation. How microglial death is regulated after activation is still unclear. We reported that exposure to lipopolysaccharide (LPS) and interleukin (IL)-13 together initially activates and then kills rat microglia in culture by a mechanism dependent on cyclooxygenase-2 (COX-2). We show here that activation of the E prostanoid receptor 2 (EP2, PTGER2) for prostaglandin E 2 mediates microglial death induced by LPS/IL-13, and that EP2 activation by agonist alone kills microglia. Both EP2 antagonists and reactive oxygen scavengers block microglial death induced by either LPS/IL-13 or EP2 activation. By contrast, the homeostatic induction of heme oxygenase 1 (Hmox1) by LPS/ IL-13 or EP2 activation protects microglia. Both the Hmox1 inducer cobalt protoporphyrin and a compound that releases the Hmox1 product carbon monoxide (CO) attenuated microglial death produced by LPS/IL-13. Whereas CO reduced COX-2 protein expression, EP2 activation increased Hmox1 and COX-2 expression at both the mRNA and protein level. Interestingly, caspase-1 inhibition prevented microglial death induced by either LPS/IL-13 or low (but not high) concentrations of butaprost, suggestive of a predominantly pyroptotic mode of death. Butaprost also caused the expression of activated caspase-3 in microglia, pointing to apoptosis. These results indicate that EP2 activation, which initially promotes microglial activation, later causes delayed death of activated microglia, potentially contributing to the resolution phase of neuroinflammation.

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Section: Ep2 Promotes Microglia Deathsupporting

confidence: 85%

Section: Ep2 Promotes Microglia Deathmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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EP2 Receptor Signaling Regulates Microglia Death

Yang

Jiang

et al. 2015

Mol Pharmacol

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“…IL-13 has been shown to significantly enhance the ER stress activated by lipopolysaccharide in microglia (Liu et al, 2010). ER stress is able to influence inflammatory signaling through modulation of the JNK and NFκB pathways.…”

Section: Discussionmentioning

confidence: 99%

Lyn kinase represses mucus hypersecretion by regulating IL-13-induced endoplasmic reticulum stress in asthma

Wang

Yang

et al. 2017

EBioMedicine

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In asthma, mucus hypersecretion is thought to be a prominent pathological feature associated with widespread mucus plugging. However, the current treatments for mucus hypersecretion are often ineffective or temporary. The potential therapeutic targets of mucus hypersecretion in asthma remain unknown. Here, we show that Lyn is a central effector of endoplasmic reticulum stress (ER stress) and mucous hypersecretion in asthma. In Lyn-transgenic mice (Lyn-TG) and wild-type (WT) C57BL/6J mice exposed to ovalbumin (OVA), Lyn overexpression attenuates mucus hypersecretion and ER stress. Interleukin 13 (IL-13) induced MUC5AC expression by enhancing ER stress in vitro. Lyn serves as a negative regulator of IL-13-induced ER stress and MUC5AC expression. We further find that an inhibitor of ER stress, which is likely involved in the PI3K p85α/Akt pathway and NFκB activity, blocked MUC5AC expression in Lyn-knockdown cells. Furthermore, PI3K/Akt signaling is required for IL-13-induced ER stress and MUC5AC expression in airway epithelial cells. The ER stress regulation of MUC5AC expression depends on NFκB in Lyn-knockdown airway epithelial cells. Our studies indicate not only a concept of mucus hypersecretion in asthma that involves Lyn kinase but also an important therapeutic candidate for asthma.

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“…Whole cell lysates were prepared as described previously (Liu et al 2010;Tsai et al 2011). After blocking, the blots were incubated with antibodies for anti-human PGK-1, TIM, enolase-1 (Santa Cruz Biotechnology), TRIM-21 (Bethyl) and ␤-actin (Millipore) in TBS with 0.1% Tween 20 for 1 h, followed by three 10-min washes in TBS with 0.1% Tween 20.…”

Section: Western Blottingmentioning

confidence: 99%