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Type 2 Cgmp-Dependent Protein Kinase Regulates Homeostasis by Blocking C-Jun N-Terminal Kinase in the Colon Epithelium

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Type 2 Cgmp-Dependent Protein Kinase Regulates Homeostasis by Blocking C-Jun N-Terminal Kinase in the Colon Epithelium Cell Death and Differentiation (2014) 21, 427–437 & 2014 Macmillan Publishers Limited All rights reserved 1350-9047/14 www.nature.com/cdd Type 2 cGMP-dependent protein kinase regulates homeostasis by blocking c-Jun N-terminal kinase in the colon epithelium R Wang1, I-K Kwon1, N Singh1, B Islam1, K Liu1, S Sridhar2, F Hofmann3 and DD Browning*,1 Analysis of knockout animals indicates that 30,50cyclic guanosine monophosphate (cGMP) has an important role in gut homeostasis but the signaling mechanism is not known. The goals of this study were to test whether increasing cGMP could affect colon homeostasis and determine the mechanism. We increased cGMP in the gut of Prkg2 þ / þ and Prkg2 À / À mice by treating with the PDE5 inhibitor Vardenafil (IP). Proliferation, differentiation and apoptosis in the colon mucosa were then quantitated. Vardenafil (Vard) treatment increased cGMP in colon mucosa of all mice, but reduced proliferation and apoptosis, and increased differentiation only in Prkg2 þ / þ mice. Vard and cGMP treatment also increased dual specificity protein phosphatase 10 (DUSP10) expression and reduced phospho-c-Jun N-terminal kinase (JNK) levels in the colon mucosa of Prkg2 þ / þ but not Prkg2 À / À mice. Treatment of Prkg2 À / À mice with the JNK inhibitor SP600125 reversed the defective homeostasis observed in these animals. Activation of protein kinase G2 (PKG2) in goblet-like LS174T cells increased DUSP10 expression and reduced JNK activity. PKG2 also increased goblet cell-specific MUC2 expression in LS174T cells, and this process was blocked by DUSP10-specific siRNA. The ability of cGMP signaling to inhibit JNK-induced apoptosis in vivo was demonstrated using dextran sodium sulfate (DSS) to stress the colon epithelium. Vard was a potent inhibitor of DSS-induced epithelial apoptosis, and significantly blocked pathological endpoints in this model of experimental colitis. In conclusion, Vard treatment activates cGMP signaling in the colon epithelium. Increased PKG2 activity alters homeostasis by suppressing proliferation and apoptosis while promoting differentiation. The PKG2-dependent mechanism was shown to involve increased DUSP10 and subsequent inhibition of JNK activity. Cell Death and Differentiation (2014) 21, 427–437; doi:10.1038/cdd.2013.163; published online 22 November 2013 Uroguanylin and guanylin are endogenous peptide hormones apoptosis at the luminal surface. Knocking out either guanylin in the intestine and colon (respectively), which trigger or GCC in mice results in reduced cGMP levels, an increased intracellular 30,50cyclic guanosine monophosphate (cGMP) proliferative compartment, increased apoptosis and reduced production by activating epithelial guanylyl cyclase C (GCC) differentiation of secretory lineage cells in the gut.8,9 More receptors.1,2 Downstream targets of cGMP include phospho- recently, Prkg2 À / À mice were also shown to exhibit crypt diesterases, ion channels and cGMP-dependent protein hyperplasia and defective differentiation, suggesting that kinases (protein kinase G (PKG)).3 Type 2 PKG is a central PKG2 mediates the homeostatic effects of guanylin/cGMP cGMP effector in the gut epithelium, and regulates the Na þ /H þ in the colon.10 À À exchanger, the Cl /HCO3 exchanger and the cystic fibrosis GCC knockout animals also show increased tumorigen- transmembrane conductance regulator.4,5 The importance of esis when treated with the mutagen azoxymethane, or when the uroguanylin/guanylin system in controlling electrolyte crossed with ApcMin/ þ mice.8,11 The mechanism responsible balance is well established, but downstream cGMP signaling for the increased susceptibility of GCC knockout animals to is also emerging as a central regulator of intestinal gut tumorigenesis is not clear. It could reflect a higher level of homeostasis. proliferation in the gut, but it could also be due to basal Homeostasis in the gut mucosa is a highly regulated inflammation resulting from a compromised epithelial barrier process involving a balance between Wnt-mediated prolifera- as recently reported in these animals.12–14 Efforts to better tion at the crypt base,6 commitment to either secretory (goblet understand the underlying signaling remain inconclusive, and enteroendocrine cells) or enterocyte lineage in the transit largely because they have relied heavily on studies of colon amplifying region,7 followed by terminal differentiation and cancer cells.10,14,15 The intestinal phenotype of knockout 1Department of Biochemistry and Molecular Biology, Cancer Research Center, Georgia Regents University, Augusta, GA, USA; 2Section of Gastroenterology and Hepatology, Department of Medicine, Georgia Regents University, Augusta, GA, USA and 3Institut fu¨r Pharmakologie und Toxikologie, Technische Universita¨tMu¨nchen, Munich, Germany *Corresponding author: DD Browning, Department of Biochemistry and Molecular Biology, CN 1164, Cancer Research Center, Georgia Regents University, 1410 Laney Walker Boulevard, Augusta, GA 30912-2100, USA. Tel: +1 706 721 9526; Fax +1 706 721 6608; E-mail: [email protected] Keywords: cGMP; PKG2; colon; DUSP10; JNK Abbreviations: b-cat, b-catenin; cGMP, 30,50cyclic guanosine monophosphate; DSS, dextran sodium sulfate; DUSP, dual specificity protein phosphatase; GCC, guanylyl cyclase C; IF, immunofluorescence; IHC, immunohistochemistry; JNK, c-Jun N-terminal kinase; PKG, protein kinase G; RT-PCR, reverse transcriptase polymerase chain reaction; Vard, Vardenafil; WT, wild-type animals Received 06.5.13; revised 18.9.13; accepted 10.10.13; Edited by JP Medema; published online 22.11.13 PKG2 inhibits JNK in the colon R Wang et al 428 mice deficient in various cGMP signaling components Results suggests that this pathway inhibits proliferation and pro- motes differentiation in the normal gut epithelium. Chal- Systemic Vard treatment increases cGMP and activates lenges associated with increasing cGMP levels in the colon PKG in the colon mucosa. To test the hypothesis that epithelium have left this hypothesis untested, and signaling PKG2 regulates homeostasis in the colon, it was necessary downstream of PKG2 in the normal colon epithelium remain to identify an efficient method for increasing cGMP in the largely unexplored. epithelial compartment. The possibility that inhibiting cGMP The aim of this study was to determine whether pharma- hydrolysis with PDE-5 inhibitors could accomplish this was cological manipulation of cGMP levels in the gut can regulate tested by intraperitoneal injection of mice with Vard (Levitra). epithelial homeostasis in wild-type (WT) mice, and to A single dose of Vard significantly increased mucosal cGMP elucidate the downstream signaling mechanism. To accom- levels in the ileum (2.1-fold, Po0.05) and colon (5.6-fold, plish this we increased cGMP in the colon epithelium by Po0.001) when measured at 6 h after injection (Figure 1a). intraperitoneal administration of the phosphodiesterase-5 The effect of Vard on the colon was rapid, with maximal inhibitor Vardenafil (Vard). In agreement with predictions cGMP levels observed at 3–4 h after administration, and this based on the analysis of knockout mice, Vard treatment slowly declined to near-basal levels after 8 h (Figure 1b). suppressed proliferation and apoptosis, but increased Vasodilator-stimulated phosphoprotein (VASP) has target secretory cell lineage differentiation in the colon epithelium. phosphorylation sites for both PKA (Ser157) and PKG Vard did not affect colon homeostasis in Prkg2 À / À mice, (Ser239), which are widely used to measure PKG activation. indicating that PKG2 is a critical part of this process. We Treatment of mice with Vard led to significant increases in the show here that activation of PKG2 by Vard led to increased level of VASP phosphorylated on Ser239 in the colon dual specificity protein phosphatase 10 (DUSP10) expres- mucosa (Figures 1c and d). These data indicate that sion and reduced the levels of phosphorylated c-Jun systemic Vard administration in mice was able to elevate N-terminal kinase (JNK) in the colon epithelium. Consistent cGMP levels high enough to activate PKG in the colon with the importance of JNK regulation in control of colon mucosa. homeostasis by cGMP, pharmacological inhibition of JNK essentially reversed the defects in PKG2-deficient animals. PKG2 activation alters homeostasis in the colon Taken together, these data support a central role for cGMP in mucosa. We previously reported that Prkg2 À / À mice suppressing apoptosis in luminal colonocytes. An important exhibit crypt hyperplasia, increased apoptosis and reduced part of the mechanism is likely to involve PKG2-dependent differentiation in the colon epithelium.10 This suggested that upregulation of DUSP10, which encodes a phosphatase that PKG2 has a critical role in homeostatic regulation in adult inhibits JNK activation. colon mucosa, but the contribution of adaptation artifacts Figure 1 Vard increases cGMP levels and PKG2 activation in the colon mucosa. (a) cGMP levels in the intestinal mucosa of CD-1 mice treated with Vard for 6 h or untreated (Ctrl). (b) cGMP levels in the proximal colon mucosa of mice over time following Vard treatment. (c) Western blot showing phospho-VASP (Ser239) in the colon mucosa of three mice with (Vard) or without (Ctrl) Vard treatment for 4 h. (d) Relative levels of phospho-VASP(Ser239) detected from western blot were quantitated and are expressed as a function of total b-actin as protein loading control. *Po0.05, ***Po0.001 Cell Death and Differentiation PKG2 inhibits JNK in the colon R Wang et al 429
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