interacts_with DB01656?
Phosphorylation of beta-arrestin2 regulates its function in internalization of beta(2)-adrenergic receptors . Beta-arrestins mediate agonist-dependent desensitization and internalization of G protein-coupled receptors . Previously , we have shown that phosphorylation of beta-arrestin1 by ERKs at DB00133 -412 regulates its association with clathrin and its function in promoting clathrin-mediated internalization of the receptor . In this paper we report that beta-arrestin2 is also phosphorylated , predominantly at residues DB00156 -383 and DB00133 -361 . DB01064 stimulation of the beta(2)-adrenergic receptor promotes dephosphorylation of beta-arrestin2 . Mutation of beta-arrestin2 phosphorylation sites to aspartic acid decreases the association of beta-arrestin2 with clathrin , thereby reducing its ability to promote internalization of the beta(2)-adrenergic receptor . Its ability to bind and desensitize the beta(2)-adrenergic receptor is , however , unaltered . These results suggest that , analogous to beta-arrestin1 , phosphorylation/dephosphorylation of beta-arrestin2 regulates clathrin-mediated internalization of the beta(2)-adrenergic receptor . In contrast to beta-arrestin1 , which is phosphorylated by P27361 and P28482 , phosphorylation of beta-arrestin2 at DB00156 -383 is shown to be mediated by casein kinase II . Recently , it has been reported that phosphorylation of visual arrestin at DB00133 -366 prevents its binding to clathrin . Thus it appears that the function of all arrestin family members in mediating internalization of G protein-coupled receptors is regulated by distinct phosphorylation/dephosphorylation mechanisms . Growth factors and glucose homeostasis in diabetic rats : effects of exercise training . To investigate the alterations of glucose homeostasis and variables of the insulin-like growth factor-1 ( DB01277 ) growth system in sedentary and trained diabetic ( TD ) rats , Wistar rats were divided into sedentary control ( SC ) , trained control ( TC ) , sedentary diabetic ( SD ) , and TD groups . Diabetes was induced by Alloxan ( 35 mg kg(-1) b.w. ) . Training program consisted of swimming 5 days week(-1) , 1 h day(-1) , during 8 weeks . Rats were sacrificed and blood was collected for determinations of serum glucose , insulin , growth hormone ( GH ) , DB01277 , and IGF binding protein-3 ( P17936 ) . Muscle and liver were removed to evaluate glycogen content . Cerebellum was extracted to determinate DB01277 content . Diabetes decreased serum GH , DB01277 , P17936 , liver glycogen , and cerebellum DB01277 peptide content in baseline condition . Physical training recovered liver glycogen and increased serum and cerebellum DB01277 peptide in diabetic rats . Physical training induces important metabolic and hormonal alterations that are associated with an improvement in glucose homeostasis and serum and cerebellum DB01277 concentrations . [ Recent advances on the studies of the platelet 's inhibition and aggregation. State of the art of new Q9H244 antagonists ] . The interaction of ADP with its platelet receptor Q9H244 plays a crucial role in platelet activation and thrombogenesis . This article reviews the pharmacology and clinical trials of specific antagonists of Q9H244 . DB00758 is a thienopyridine with proven antithrombotic efficacy , but it has some important drawbacks : i ) it is a pro-drug that needs to be metabolized to its active metabolite ; ii ) it has a delayed onset and offset of action ; iii ) there is high inter-individual variability in pharmacological response . Prasugrel is also a thienopyridine , with faster onset of action and more uniform inhibition of platelet function compared to clopidogrel , accounting for lower incidence of ischemic events in patients with acute coronary syndromes ( ACS ) undergoing percutaneous coronary intervention ( P05154 ) and higher incidence of both non-CABG ( Coronary Artery Bypass Grafting ) related bleeding complications . Two direct and reversible Q9H244 antagonists , cangrelor and ticagrelor , are characterized by rapid onset and reversal of platelet inhibition . DB06441 did not prove superior to clopidogrel in preventing thrombotic events in patients undergoing P05154 . DB08816 proved to be superior to clopidogrel in preventing major adverse cardiac events in ACS patients , but was , like prasugrel , was associated with higher frequency of non-CABG-related bleeding complications . A shorter period of drug discontinuation before surgery was necessary in ticagrelor-treated patients compared to clopidogrel-treated patients to limit the severity of post-surgical bleeding . Evidence for a link between histone deacetylation and Ca²+ homoeostasis in sphingosine-1-phosphate lyase-deficient fibroblasts . Embryonic fibroblasts from Q14703 ( sphingosine-1-phosphate ) lyase-deficient mice [ Sgpl1-/- MEFs ( mouse embryonic fibroblasts ) ] are characterized by intracellular accumulation of Q14703 , elevated cytosolic [Ca2+]i and enhanced Ca2+ storage . Since Q14703 , produced by sphingosine kinase 2 in the nucleus of MCF-7 cells , inhibited HDACs ( histone deacetylases ) [ Hait , Allegood , Maceyka , Strub , Harikumar , Singh , Luo , Marmorstein , Kordula , Milstein et al. ( 2009 ) Science 325 , 1254-1257 ] , in the present study we analysed whether Q14703 accumulated in the nuclei of Q14703 lyase-deficient MEFs and caused HDAC inhibition . Interestingly , nuclear concentrations of Q14703 were disproportionally elevated in Sgpl1-/- MEFs . HDAC activity was reduced , acetylation of histone 3-Lys9 was increased and the HDAC-regulated gene P38936 cyclin-dependent kinase inhibitor was up-regulated in these cells . Furthermore , the expression of Q13547 and O15379 was reduced in Sgpl1-/- MEFs . In wild-type MEFs , acetylation of histone 3-Lys9 was increased by the Q14703 lyase inhibitor 4-deoxypyridoxine . The non-specific HDAC inhibitor trichostatin A elevated basal [Ca2+]i and enhanced Ca2+ storage , whereas the Q13547 /2/3 inhibitor DB05651 elevated basal [Ca2+]i without influence on Ca2+ storage in wild-type MEFs . Overexpression of Q13547 or Q92769 reduced the elevated basal [Ca2+]i in Sgpl1-/- MEFs . Taken together , Q14703 lyase-deficiency was associated with elevated nuclear Q14703 levels , reduced HDAC activity and down-regulation of HDAC isoenzymes . The decreased HDAC activity in turn contributed to the dysregulation of Ca2+ homoeostasis , particularly to the elevated basal [Ca2+]i , in Sgpl1-/- MEFs . Q9H244 receptor signalling towards P31749 proceeds through P08069 cross-talk and requires activation of Src , Pyk2 and Rap1 . Previously it was shown that stimulation of the Q9H244 receptor activates P31749 signalling in P13671 glioma cells [ K. Van Kolen and H. Slegers , J. Neurochem. 89 , 442. ] . In the present study , the mechanisms involved in this response were further elucidated . In cells transfected with the Gbetagamma-scavenger beta- O14965 / P25098 or Rap1GAPII , stimulation with 2MeSADP failed to enhance P31749 phosphorylation demonstrating that the signalling proceeds through Gbetagamma-subunits and Rap1 . Moreover , Rap1-GTP pull-down assays revealed that Q9H244 receptor stimulation induced a rapid activation of Rap1 . Treatment of cells with the Ca2+ chelator BAPTA-AM and inhibition of Src and O14939 with Q99463 or 1-butanol , respectively , abrogated Q9H244 receptor-mediated activation of Rap1 and P31749 . In addition inhibition of PKCzeta decreased basal and 2MeSADP-stimulated phosphorylation of P31749 indicating a role for this PKC isoform in P31749 signalling . Although the increased P31749 phosphorylation was abolished in the presence of the P08069 tyrosine kinase inhibitor AG 1024 , 2MeSADP did not significantly increase receptor phosphorylation . Nevertheless , phosphorylation of a 120 kDa P08069 -associated protein was observed . The latter protein was identified by MALDI-TOF/TOF-MS as the proline-rich tyrosine kinase 2 ( Pyk2 ) that co-operates with Src in a O14939 -dependent manner . Consistent with the signalling towards Rap1 and P31749 , activation of Pyk2 was abrogated by Ca2+ chelation , inhibition of O14939 and P08069 tyrosine kinase activity . In conclusion , the data reveal a novel type of cross-talk between Q9H244 and P05019 receptors that proceeds through Gbetagamma- , Ca2+-and O14939 -dependent activation of the Pyk2/Src pathway resulting in GTP-loading of Rap1 required for an increased P31749 phosphorylation . The role of MAPK and Nrf2 pathways in ketanserin-elicited attenuation of cigarette smoke-induced P10145 production in human bronchial epithelial cells . Cigarette smoking is a major risk factor in chronic obstructive pulmonary disease ( P48444 ) with chronic airway inflammation as a key feature . Blockade of serotonin receptor 2A ( 5-HTR(2A) ) with ketanserin has been found to improve lung function in P48444 patients . Furthermore , ketanserin has been shown to possess anti-inflammatory properties in vivo . In this study , we investigated the antioxidative and anti-inflammatory properties of ketanserin and its underlying mechanism of action on cigarette smoke-induced interleukin ( IL ) -8 release in vitro . Primary normal human bronchial epithelial cells and human bronchial epithelial cell line ( BEAS-2B ) were treated with or without ketanserin prior to exposure to cigarette smoke medium ( CSM ) . Exposure to CSM caused elevation of both mRNA and release of P10145 with increased phosphorylation of p38 and extracellular signal-regulated kinases 1 and 2 ( P27361 /2 ) . Consistently , CSM-induced P10145 release was blocked by SB203580 , U0126 , or Q02750 small interfering RNA ( siRNA ) but not SP600125 . On the other hand , CSM caused a dose-dependent decrease in the ratio of reduced glutathione to oxidized glutathione ( rGSH/GSSG ) together with an increased translocation of Nrf2 to the nucleus demonstrated by Western blot analysis . Knock down of Nrf2 by siRNA completely blocked CSM-induced P10145 release . Ketanserin suppressed CSM-induced P10145 release by inhibiting p38 , P27361 /2 MAPK , and Nrf2 signaling pathways and partially inhibited CSM-induced reduction of rGSH/GSSG ratio . Our data demonstrated the novel antioxidative and anti-inflammatory role of ketanserin via the Nrf2 signaling pathway in CSM-exposed human bronchial epithelial cells . This may open up new perspectives in the development of novel therapeutic targets in the treatment of cigarette smoke-related P48444 . P01308 -like growth factor binding protein-3 interacts with the thyroid hormone receptor α1 and modulates transcription of thyroid hormone responsive gene . OBJECTIVE : To study the interaction between insulin-like growth factor binding protein-3 ( P17936 ) and thyroid hormone receptor α1 ( TRα1 ) and the modulatory effect of P17936 on transcription of the thyroid hormone responsive gene . METHODS : The interaction between P17936 and TRα1 was detected with glutathione-S-transferase pull-down method , co-immunoprecipitation , fluorescence resonance energy transfer test . The cellular distribution of these two proteins was observed by confocal laser scanning microscopy . The effect of P17936 on the growth hormone promoter activity stimulated by triiodothyronine ( DB00279 ) was determined by dual-luciferase reporter assay . RESULTS : P17936 interacted with TRα1 both in vivo and in vitro . P17936 and TRα1 were shown to co-localize in the nucleus of P29320 -293 cells . The overexpressed P17936 inhibited the growth hormone promoter activity stimulated by DB00279 ( P < 0.01 ) . CONCLUSIONS : P17936 interacts with TRα1 and inhibits DB00279 responsive gene transcription . This finding further confirms the insulin-like growth factor-independent role of P17936 in the nucleus . Design and synthesis of 3,5-disubstituted-1,2,4-oxadiazoles as potent inhibitors of phosphodiesterase4b2 . A series of 3,5-disubstituted-1,2,4-oxadiazoles has been prepared and evaluated for phosphodiesterase inhibition ( PDE4B2 ) . Among the prepared 3,5-disubstituted-1,2,4-oxadiazoles , compound 9a is the most potent inhibitor ( PDE4B2 IC(50) = 5.28 μm ) . Structure-activity relationship studies of 3,5-disubstituted-1,2,4-oxadiazoles revealed that substituents 3-cyclopentyloxy-4-methoxyphenyl group at 3-position and cyclic ring bearing heteroatoms at 5-position are important for activity . Molecular modeling study of the 3,5-disubstituted-1,2,4-oxadiazoles with Q07343 has shown similar interactions of 3-cyclopentyloxy-4-methoxyphenyl group ; however , heteroatom ring is slightly deviating when compared to DB01791 . 3-(3-Cyclopentyloxy-4-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole ( 9a ) exhibited good analgesic and antiinflammatory activities in formalin-induced pain in mice and carrageenan-induced paw edema model in rat . Cholecystokinin ( CCK ) stimulates aldosterone secretion from human adrenocortical cells via CCK2 receptors coupled to the adenylate cyclase/protein kinase A signaling cascade . Cholecystokinin ( CCK ) IS a regulatory peptide that acts via two receptor subtypes , P32238 and P32239 . RT-PCR demonstrated the expression of both P32238 and P32239 in the zona glomerulosa ( ZG ) , but not zona fasciculata-reticularis cells of the human adrenal cortex . CCK and the P32239 agonist pentagastrin enhanced basal aldosterone secretion from ZG cells without affecting cortisol production from zona fasciculata-reticularis cells . The aldosterone response to CCK and pentagastrin was suppressed by a P32239 antagonist , but not by a P32238 antagonist . DB00183 evoked a sizeable DB02527 , but not inositol triphosphate , response from ZG cells , whereas CCK plus P32239 antagonist was ineffective . The DB02527 response to pentagastrin was abrogated by P32239 antagonist or the adenylate cyclase inhibitor SQ-22536 , and the aldosterone response was abolished by both SQ-22536 and the protein kinase A inhibitor H-89 . Both CCK and pentagastrin increased steroidogenic acute regulatory protein mRNA expression in ZG cells ; the effect was abrogated by P32239 antagonist . We conclude that CCK exerts secretagogue action on human ZG cells , acting through CCK2-Rs coupled to the adenylate cyclase/protein kinase A signaling cascade , which , in turn , stimulates the expression of steroidogenic acute regulatory protein , the rate-limiting step of steroidogenesis . Targeted cytotoxic analog of luteinizing hormone-releasing hormone ( P01148 ) , AEZS-108 ( AN-152 ) , inhibits the growth of DU-145 human castration-resistant prostate cancer in vivo and in vitro through elevating P38936 and ROS levels . Management of castration-resistant prostate cancer ( CRPC ) is challenging due to lack of efficacious therapy . DB00044 -releasing hormone analogs appear to act directly on cells based on the P01148 receptors on human prostate adenocarcinoma cells . We explored anticancer activity of a cytotoxic analog of P01148 , AEZS-108 consisting of P01148 agonist linked to doxorubicin . Nude mice bearing DU-145 tumors were used to compare antitumor effects of AEZS-108 with its individual constituents or their unconjugated combination . The tumor growth inhibition of conjugate was greatest among treatment groups ( 90.5 % inhibition vs. 41 % by [D-Lys(6)] P01148 +DOX ) . The presence of P01148 receptors on DU-145 cells was confirmed by immunocytochemistry . In vitro , AEZS-108 significantly inhibited cell proliferation ( 61.2 % inhibition ) and elevated apoptosis rates ( by 46 % ) . By the detection of the inherent doxorubicin fluorescence , unconjugated doxorubicin was seen in the nucleus ; the conjugate was perinuclear and at cell membrane . Autophagy , visualized by GFP-tagged p62 reporter , was increased by AEZS-108 ( 7.9-fold vs. 5.3-fold by DOX+[D-Lys(6)] P01148 . AEZS-108 more effectively increased reactive oxygen species ( ROS , 2-fold vs. 1.4-fold by DOX+[D-Lys(6)] P01148 ) and levels of the apoptotic regulator P38936 in vivo and in vitro . We demonstrate robust inhibitory effects of the targeted cytotoxic P01148 analog AEZS-108 on P22888 positive castration-resistant prostate cancer cells . DB00796 inhibits Toll-like receptor expression and activity both in vitro and in vivo . INTRODUCTION : Toll-like receptors play an important role in the innate immune system and are found to be crucial in severe diseases like sepsis , atherosclerosis , and arthritis . O60603 and O00206 expression is upregulated in the inflammatory diseases . Angiotensin II in addition to stimulating vasoconstriction also induces an increase in ROS and a proinflammatory phenotype via AT(1)R . P30556 blocker ( ARB ) , widely used as an antihypertensive drug , has been reported to also have anti-inflammatory effects . Thus , we investigated whether an ARB exerts anti-inflammatory effects via inhibiting O60603 and O00206 expression . METHODS AND RESULTS : Monocytes were isolated from healthy human volunteers and treated with the synthetic lipoprotein Pam3CSK4 or LPS in the absence or presence of candesartan . Pretreatment of human monocytes with candesartan significantly decreased Pam3CSK4 or LPS induced O60603 and O00206 expression of both mRNA and protein levels ( P < 0.05 vs. control ) along with decrease in the activity of NF-kappaB and the expression of IL-1beta , P05231 , P01375 , and P13500 . Furthermore , candesartan treated mice show decreased O60603 and O00206 expression compared to vehicle control mice . CONCLUSION : Pam3CSK4 and LPS induced O60603 and O00206 expression at mRNA and protein levels are inhibited by candesartan both in vitro and in vivo . Thus , we define a novel pathway by which candesartan could induce anti-inflammatory effects . Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence . Mitochondria are dynamic organelles that continuously change their shape through fission and fusion . Disruption of mitochondrial dynamics is involved in disease pathology through excessive reactive oxygen species ( ROS ) production . Accelerated cellular senescence resulting from cigarette smoke exposure with excessive ROS production has been implicated in the pathogenesis of chronic obstructive pulmonary disease ( P48444 ) . Hence , we investigated the involvement of mitochondrial dynamics and ROS production in terms of cigarette smoke extract ( CSE ) -induced cellular senescence in human bronchial epithelial cells ( HBEC ) . Mitochondrial morphology was examined by electron microscopy and fluorescence microscopy . Senescence-associated β-galactosidase staining and P38936 Western blotting of primary HBEC were performed to evaluate cellular senescence . Mitochondrial-specific superoxide production was measured by MitoSOX staining . Mitochondrial fragmentation was induced by knockdown of mitochondrial fusion proteins ( O60313 or Mitofusins ) by small-interfering RNA transfection . DB06151 and Mito-TEMPO were used as antioxidants . Mitochondria in bronchial epithelial cells were prone to be more fragmented in P48444 lung tissues . CSE induced mitochondrial fragmentation and mitochondrial ROS production , which were responsible for acceleration of cellular senescence in HBEC . Mitochondrial fragmentation induced by knockdown of fusion proteins also increased mitochondrial ROS production and percentages of senescent cells . HBEC senescence and mitochondria fragmentation in response to CSE treatment were inhibited in the presence of antioxidants . CSE-induced mitochondrial fragmentation is involved in cellular senescence through the mechanism of mitochondrial ROS production . Hence , disruption of mitochondrial dynamics may be a part of the pathogenic sequence of P48444 development . First intracellular loop of the human cholecystokinin-A receptor is essential for cyclic AMP signaling in transfected P29320 -293 cells . Cholecystokinin ( CCK ) -A and CCK-B receptors are highly homologous members of the seven transmembrane domain G-protein-coupled receptor superfamily . Genes of both receptors contain five exons and share a similar exon-intron organization . To determine the structural basis of P32238 ( P32238 ) functionally coupled to Gs , a series of chimeric mutants were constructed by replacing exons of human P32239 ( P32239 ) , from the second to the fifth ( last ) exon , with human P32238 counterparts . Binding and signal transduction properties of wild-type and chimeric receptors were examined in stably transfected P29320 -293 cells . Chimeric receptors that maintained high affinity binding to CCK exhibited dose-dependent increases in intracellular calcium mobilization similar to both wild-type receptors . However , only the wild-type P32238 and chimeric mutants containing the second exon of P32238 were able to mediate significantly greater increases in intracellular DB02527 content and adenylyl cyclase activity compared with wild-type P32239 . A P32239 mutant was further constructed by replacing five amino acids , DB00145 - DB00149 - DB00133 - DB00125 -( DB00125 )- DB00149 , in the first intracellular loop with the corresponding five P32238 specific amino acids , DB00167 - DB00125 - DB00174 -Lys-( DB00125 )- DB00134 . The resultant receptor maintained high affinity binding to both CCK and gastrin and dose-dependent calcium responses similar to wild-type P32239 . However , this first intracellular loop mutant also gained positive DB02527 responses to both sulfated CCK-8 and gastrin-17 with EC50 values of 8.5 +/- 1 nM and 23 +/- 7 nM , respectively . These data suggest that the first intracellular loop of P32238 is essential for coupling to Gs and activation of adenylyl cyclase signal transduction cascade . Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent DB05876 inhibitors . 2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative ( 2 ) was found to be a new DB05876 inhibitor with moderate Q07343 activity ( IC50=150 nM ) . A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized . Among these , 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative ( 18 ) showed potent Q07343 inhibitory activity ( IC50=25 nM ) . Finally , N-propylacetamide derivative ( 31b ) was determined as a potent inhibitor for both Q07343 ( IC50=7.5 nM ) and P01375 -α production in mouse splenocytes ( IC50=9.8 nM ) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice ( ID50=18 mg/kg ) . The binding mode of the new inhibitor ( 31e ) in the catalytic site of Q07343 is presented based on an X-ray crystal structure of the ligand-enzyme complex . Anti-inflammatory properties of Septilin in lipopolysaccharide activated monocytes and macrophage . In vivo studies have suggested the immunomodulatory properties of Septilin , an herbal preparation . This drug is being used against various types of inflammatory disorders . However , the mechanism of action of Septilin in the modulation of inflammation is not explored using suitable in vitro models . Hence , we decided to study the modulatory role of Septilin in lipopolysaccharide ( LPS ) mediated signaling in macrophage and monocyte cells . It was observed from the present study that by employing tumor necrosis factor α ( P01375 -α ) bioassay and reverse transcription-polymerase chain reaction ( RT-PCR ) , Septilin inhibited P01375 -α production in LPS ( 1 μg/mL ) stimulated RAW 264.7 cells ( p < 0.05 ) . 80 % inhibition of P01375 -α was observed even at 2.5 % Septilin . Septilin at all the concentrations tested could also significantly block the LPS mediated nitric oxide ( NO ) production ( p < 0.01 ) and expression of inducible NO synthase ( P35228 ) gene . LPS mediated interleukin 6 ( P05231 ) and P10145 production was also blocked by Septilin at the concentrations tested . This herbal preparation could also inhibit cycloxygenase 2 ( P35354 ) activity and suppression of P35354 and phosphodiesterase 4 B ( Q07343 ) mRNA expression in a concentration dependent manner . Taken together , these findings from the present in vitro study suggest the anti-inflammatory and immunomodulatory properties of Septilin . Phosphodiesterase-4 influences the PKA phosphorylation status and membrane translocation of G-protein receptor kinase 2 ( P25098 ) in P29320 -293beta2 cells and cardiac myocytes . Membrane-recruitment of P25098 ( G-protein receptor kinase 2 ) provides a fundamental step in the desensitization process controlling GPCRs ( G-protein-coupled receptors ) , such as the beta2AR ( beta2-adrenergic receptor ) . In the present paper , we show that challenge of P29320 -293beta2 [ human embryonic kidney cells stably overexpressing the FLAG-tagged beta2AR-GFP ( green fluorescent protein ) ] cells with the beta-adrenoceptor agonist , isoprenaline , causes P25098 to become phosphorylated by PKA ( DB02527 -dependent protein kinase ) . This action is facilitated when DB02527 -specific DB05876 ( phosphodiesterase-4 ) activity is selectively inactivated , either chemically with rolipram or by siRNA ( small interfering RNA ) -mediated knockdown of Q07343 and Q08499 . DB05876 -selective inhibition by rolipram facilitates the isoprenaline-induced membrane translocation of P25098 , phosphorylation of the beta2AR by P25098 , membrane translocation of beta-arrestin and internalization of beta2ARs . DB05876 -selective inhibition also enhances the ability of isoprenaline to trigger the PKA phosphorylation of P25098 in cardiac myocytes . In the absence of isoprenaline , rolipram-induced inhibition of DB05876 activity in P29320 -293beta2 cells acts to stimulate PKA phosphorylation of P25098 , with consequential effects on P25098 membrane recruitment and P25098 -mediated phosphorylation of the beta2AR . We propose that a key role for DB05876 enzymes is : ( i ) to gate the action of PKA on P25098 , influencing the rate of P25098 phosphorylation of the beta2AR and consequential recruitment of beta-arrestin subsequent to beta-adrenoceptor agonist challenge , and ( ii ) to protect P25098 from inappropriate membrane recruitment in unstimulated cells through its phosphorylation by PKA in response to fluctuations in basal levels of DB02527 . Targeting interleukin-6 in inflammatory autoimmune diseases and cancers . P05231 ( P05231 ) is a pleiotropic cytokine with significant functions in the regulation of the immune system . As a potent pro-inflammatory cytokine , P05231 plays a pivotal role in host defense against pathogens and acute stress . However , increased or deregulated expression of P05231 significantly contributes to the pathogenesis of various human diseases . Numerous preclinical and clinical studies have revealed the pathological roles of the P05231 pathway in inflammation , autoimmunity , and cancer . Based on the rich body of studies on biological activities of P05231 and its pathological roles , therapeutic strategies targeting the P05231 pathway are in development for cancers , inflammatory and autoimmune diseases . Several anti- P05231 / P05231 receptor monoclonal antibodies developed for targeted therapy have demonstrated promising results in both preclinical studies and clinical trials . DB06273 , an anti- P05231 receptor antibody , is effective in the treatment of various autoimmune and inflammatory conditions notably rheumatoid arthritis . It is the only P05231 pathway targeting agent approved by the regulatory agencies for clinical use . DB09036 , an anti- P05231 antibody , has been shown to have potential benefits treating various human cancers either as a single agent or in combination with other chemotherapy drugs . Several other anti- P05231 -based therapies are also under clinical development for various diseases . P05231 antagonism has been shown to be a potential therapy for these disorders refractory to conventional drugs . New strategies , such as combination of P05231 blockade with inhibition of other signaling pathways , may further improve P05231 -targeted immunotherapy of human diseases . Cross-talk between PKA-Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . DB01656 , a phosphodiesterase (PDE)4-selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up-regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up-regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners . We also found that protein kinase A catalytic subunit β ( PKA-Cβ ) and nuclear factor-κB ( NF-κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA-Cβ phosphorylates p65 in a DB02527 -dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA-Cβ-induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .