2
`W1
`GA699
`Supp .1
`v • . 120
`no. 5
`
`rt[lQ01 Volyme 120 • Nu~er 5 • Suppl 1
`
`UC San Diego
`Received on: 05-15-01
`.C./CJ337fZ.. (§
`~
`BP..oWIV
`
`..
`
`

`

`oastroenterolo
`
`Offlcia~ournal of the American Gastroenterological Association
`
`Editor
`Daniel ' Pooolsky
`~i.tSSochttem General Hospital
`Bosron, ~assachusens
`
`Senior
`Assoc:iate Editor
`J. Thomas l..aMonr
`B~rh Israel Deaconess
`Medical Cemer
`Bosron, Massachusens
`
`Richard i· Blumberg
`Brigham'& Women's Hospiral
`Bosron, ~iassochusens
`Michael bmilleri
`Mayo Clinic
`Rochesrtt, Minnesoca
`Jules L. biensmg
`Massachusem General Hospiral
`Boston, tlassachuserrs
`Fred S. GoreliCk
`West H.rven VA Medocal Cemer
`West H'l\•en. Connecrocur
`Neil Kaplowirz
`USC School of Medicine
`Los Angeles, C~lifornia
`
`Associate Editors
`T. Jake Liang
`Nauonal lnsrirures of Healrh
`Bethesda, Maryland
`Jeffrey B. Monhews
`Beth Israel Deaconess Medical Center
`Bosron, MassJchusem
`Ann Ouyang
`Penn Smte College of Medicine
`Hershey, Pennsylvanoa
`Ani! K. Rusrgi
`University of Pennsylvania
`School of Medicine
`Philadelphia, Pennsylvania
`
`Editorial Staff
`Deborah Zimmer, t\lanaging Editor
`Nikolera Dineen, Senior Manmrript Coordinator
`Gilbert Ebner, Stnior Manuscript Coordinator
`T hoba Khum:tlo, Manuscript c-dinator
`Erin Loughran, Manusmpt Coordhtator
`Axel Morales, lllamtsrript Coordinator
`Leah Passfield , Manuscript Coordinator
`Joanna Karogiannis, Editorial lwiitam
`
`Guido N.). Tyrgar
`Academic Medical Cenrer
`Amsrerdam, The Netherlands
`T imorhy C. Wang
`University of MassachusettS Medical Cencer
`Worcester, Massachuserrs
`Associate Editor for Nutrition
`Samuel Kldn
`Washington University School of Medicine
`Sr. Louis, Missouri
`Consulting Blostatlatlclans
`Endel John Orav
`Bos.ron, Massachuserrs
`YuChiao Chang
`Boston, Massachuserrs
`
`This :\lonth in K"ren E. Kim
`GASTROENTEROLOGY Chicago, Illinois
`Image tJ/ the Jlfomh Sanjiv Chopra
`Bosron, Massachusetts
`
`Special Section Editors
`Gastrotllftrology
`News
`
`Ani! K. Rusrgi
`Philadelphia, Pennsylvania
`
`Selected SmnmarieJ Henry ). Binder
`New Haven. Connecricur
`Editorial Board
`
`Prim and Altdia Rwierus
`
`lawrence S. Friedman
`Bosron, Massachusetts
`
`Nczham Afdhal, Bosron, Massachuserrs
`Guodo Adler, Ulm, Germany
`James M. Anderson, New Haven, Connecricur
`John Baillie, Durham, Norrh Carolina
`laurence M. Blendis, Tel Aviv, Israel
`Roberc S. Bresalier, Derroir, Michig~n
`Markus W. BUchler, Bern. Switzerland
`Alan Charney. New York, New York
`Tsutomu Chiba, Kyoro, J•p•n
`Ray E. Clouse, St. Louis, Missouri
`Stephen Collins, Hamilron, Onrdrio, Canoda
`Fabio Comonelli, Charlonesville, Virginia
`Nocholas Davidson, Sr. Louis, Missouri
`Joanne Donovan, Boston, Massachuserrs
`Douglas A. Drossman, Chapel H ill, Norrh Carolino
`J. Greg Firz, Denver, Colorado
`Eileen rriedman, Syracuse, New York
`Richard Grand, Boston, Massachusetts
`Peter C. Hayes, Edinburgh, Scodand. United Kmdgom
`Gail Ht>Chr, Chicago, Illinois
`Toshifumi Hobi, Tokyo, Japan
`Jay H. Hoofnagle, Berhesda, Maryland
`Srephen P. James, Berhesda, Mor}•lanJ
`Rochard A. Kourek, Seattle, \'(fashingron
`Officers of the American Gastroenterologlcal Association
`Pmidmt-E!rt:t V~canc
`Pmidem Jon I. Isenberg
`San Diego, California
`
`Ernsr J. Kuipers, Rorrerdam, The Nerherlands
`Nicholas F. LaRusso, Rochesrer, Minnesota
`Didier Lebrec, Ciichy, France
`Adrian Lee, Sydney, Ausrralia
`Daniel Louvard, Paris, France
`J ames L. Madara, Aclanra, Georgia
`Gabriel Makhlouf, Richmond, Virginia
`Peter Malferrheiner, Magdeburg, Germany
`Emeran A. Mayer, Los Angeles, California
`J uanita Merchant, Ann Arbor, Michigan
`Howard Mertz, Nashville, Tennessee
`Kunio Okuda, Chiba, Japan
`Henry P. Parkman, Pholadelphia, Pennsylvania
`Charalabos Porhoulakos, Bosron, Massachusem
`Lawrie W. Powell, Brisb>ne, Auscmlia
`Linda Rabeneck, Houston, Texas
`Daniel Rach molewirz, Jerusalem, Israel
`Roberr Riddell, Hnmilron, Ontario, Canada
`Nobuhiro Saco, Tokyo, Japan
`)iirgcn Scholmerich, Regensburg, G .. rmany
`lloyd R. Sutherland, Calgary, Alberta, Canada
`Jan Tack, Leuven, Belgium
`Perer G. Traber, Philadelphia, Pennsylvania
`
`~/OJ :!:~961~~~8 ~
`
`ire Pmidmt Marrin Brurman
`San Froncisco, Calofornia
`
`Scmtr~r; joanne A. P. Wilson
`Durham, Norrh Carolina
`
`Treasurer MarkS. McPhee
`Kans.-.s Ciry, Missouri
`
`Pu, llshP.d bv W. B. Saunders Company, The Curtis Cente r, Independe nce Square West, Philade lphia, Pennsylvania 1.9106-3399
`
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`GASTROENTEROLOGY: GASTAB 120(5) A1-A766 (200l.)
`lSSN OOl.G-5085
`© 2001 by the American Gastroenterologlcal Association
`
`

`

`PROGRAM OF THE. ANNUAL MEETING OF
`
`THE AMERICAN
`GASTROENTEROLOGICAL ASSOCIATION
`AND
`
`DIGESTIVE DISEASE WEEK
`
`May 20 -23, 2001
`Atlanta, Georgia
`
`This supplement contains rhe abstracrs and program of the American Gasrroencerologi(cid:173)
`cal Association, American Association for rhe Study of Liver Disease, American Society
`for Gasrroincestinal Endoscopy (program only), and the Society for Surgery of the
`Alimentary T ract. Noce: Program sessions are listed in chronological order each day.
`
`

`

`PROGRAM
`
`8:15
`1193
`
`8:30
`#94
`
`8:45
`1195
`
`9:00
`1196
`
`9:15
`1197
`
`Peptone Stimulates CCK-re leasing Peptide
`(OBI) Gene Expression by Activating Intestinal
`Submucosal Cholinergic Neurons Through the
`Release of Intestinal Se.rotonin.
`I Song, Y Li, K Choi, H·R Kim, C Owyang, Ann
`Arbor·, MI.
`
`The Importance of NK1-receptor Mediated
`Mechanisms in the Regulation of Visceral
`Hypersensitivity.
`Matthew S. Gibson, Debra Sutkowslci-Markmann,
`Beverley Greenwood van-Meerveld, Deerfield, IL,
`Oklahoma City, OK.
`
`Differential Signaling by Muscarinic m3 and
`m2 Receptors Determines Sustained Myosin
`Light Chain (MLC) Phosphorylation and
`Smooth Muscle Contraction.
`Karnam S. Murthy, Huiping Zhou, Gabriel M.
`Makhlouf, Richmond, VA.
`
`IGFBP-5 S timulates Growth of Human
`Intestinal Smooth Muscle Independently of
`IGF-1 by Activation of p38- and p42/44-MAP
`Kinases.
`John F. Kuemmerle, Richmond, VA.
`
`A Dominant Negative Approach For
`Characterization of The G-Proteins Mediating
`His tamine H 2 Receptor Signaling.
`Lidong Wang, Meizhi Wang, Kenneth Butler,
`Annette Gilchrist, Heidi E. Hamm, John Del Valle,
`Ann Arbor, MI, Chicago, IL.
`
`AGA Distinguished Abstract Plenary Session:
`Immunology, Microbiology and Inflammatory
`Bowel Disease
`8:00AM-9:30AM
`
`160W
`Georgia World Congress Center
`
`Chairs: Martin Kagnoff, Richard Blumberg, Stephen
`Hanauer
`
`Sponsored by: Immunology, Microbiology and
`Inflammatory Bowel Disease
`
`IMMUNOLOGY, MICROBIOLOGY AND
`INFLAMMATORY BOWEL DISEASE
`8:00
`1#98
`
`A Randomize d, Double-Blind, Placebo-
`Con t r olle d Trial Of Subcutaneous Etanercept
`(p75 Souble Tumor Necros is Factor:FC Fusion
`Protein) In The Treatment Of Moderate To
`Severe Crohn's Disease.
`WiJiiam J. Sandborn, Stephen B. Hanauer,
`Seymour Katz, Michael Safdi, Douglas C. Wolf,
`Richard D. Baerg, William J . Tremaine, Therese
`Johnson, Nancy Diehl, Alan R. Zinsmeister,
`Atlanta, GA, Chicago, IL, Cincinnati, OH, Long
`Island. NY, Rochester, MN, Tacoma, WA.
`
`8:18
`1199
`
`Maintenance Infliximab (Remicade) Is Safe,
`Effective and Steroid-Sparing in Crohn's
`Disease: Pre liminary Results from the Accent I
`Trial.
`Stephen B. Hanauer, Gary R. Lichtenstein, J -F
`Columbel, Lloyd Mayer, Stephan Schreiber, Daniel
`Rachmilewicz, Doug Wolf, Helmut Malchow,
`Michael Safdi, Brian Feagan, Allan Olson, Paul
`Rutgeer ts, Atlanta, GA, Chicago, IL, Kiel,
`Germany, Leuven, Belgium, Leverkusen,
`Germany, Lille, France, London, Canada, Malvern,
`PA, New York, NY, Philadelphia, PA, Tel Aviv,
`Israel.
`
`8:36
`#100
`
`8:52
`#101
`
`9:10
`#102
`
`Type I Helicobacter P;y/ori Lipopolysaccharide
`Activates Toll-Like Receptor 4-Mediated
`Intracellular Signaling and Up-Regulates Mod
`Oxidase Expressed in Gastric Pit Cells
`Kazuhito Rokutan, Tsukasa Kawahara, Shigetada
`Teshima, Tomoko Kawai, Toshiro Sugiyama, Keiya
`Nakamura, Kyoto, Japan, Sapporo, Japan,
`. Tokushima, Japan.
`
`The Intrinsic Inhibitors of JAK/STAT Pathway,
`CIS3/SOCS3/SSI3 and JAB/SOCSl/SSil, Play a
`Negative Regulatory Role in STAT3 Activation
`and Intestinal Inflammation.
`Asuka Suzulci, Keiichi Mitsuyama, Nobuo
`Tomiyasu, Kosuke Takagi, Atsushi Toyonaga,
`Alcihiko Yoshimura, Michio Sata, Kurume, Japan.
`
`T Cell Activation Instructs Epithelial Lineage
`Development by Inducing Paneth Cell
`Expansion and Cryptdin Production in
`Intestinal Crypts.
`Ziad Alna<ljim, Steve M. Colm, Tolcioshi Ayabe,
`Sam Biafora, Andre Ouellette, Terrence A.
`Barrett, Charlottesville, VA, Chicago, IL, Irvine,
`CA.
`
`AGA Distinguished Abstract Plenary Session:
`Intestinal Disorders
`8:00AM-9:30AM
`
`255W
`Georgia World Congress Center
`
`Chairs: Kim Barrett, Peter Traber
`
`Sponsored by: Intestinal Disorders
`
`INTESTINAL DISORDERS
`
`8:00
`1103
`
`8:18
`IH04
`
`8:38
`#105
`
`8:52
`#106
`
`The Prevalence of Coeliac Disease in Patients
`Fulfilling the ROME ll Criteria for Irritable
`Bowel Syndrome: A Case Control Study
`DavidS. Sanders, Martyn J. Carter, David P.
`Hurlstone, Alison Pearce, Anthony Milford-Ward,
`Mark E. McAlindon, Alan J . Lobo, Sheffield,
`United Kingdom.
`
`Tegaserod Provides Relief of Symptoms in
`Female Patients with Irritable Bowel
`Syndrome (ffiS) Suffering from Abdominal
`Pain and Discomfort, Bloating and
`Constipation.
`Marty Lefkowitz, Gregory Ligozio, Kathie Glebas,
`Joan E. Heggland, Peter C. Rueegg, Basel,
`Switzerland, East Hanover, NJ.
`The Panetb Cell + a-defensin Cryptdin 3
`Induces a Cat+ -dependent Secretion of IL-8 in
`Model Intestinal Epithelia
`Peter 0. Simon, Patricia Lin, Andrew T. Gerwitz,
`Didier Merlin, Don P. Satchell, Michael E. Selsted,
`AndreJ. Ouellette, James L. Madara, Wayne I.
`Lencer, Atlanta, GA, Boston, MA, Irvine, CA.
`
`Protein Phosphatase 2A Participates in Effect
`of Epidermal Growth Factor on
`Phosphatidylinositol 3-Kinase: Role in Ion
`Transport.
`Jimmy Y. C. Chow, Kim E. Barrett, San Diego,
`CA.
`
`Identification of a DNA-Binding Protein with
`9:10
`ln07 Multiple Zinc Fingers Required for
`Transcription of the Secre tin Gene
`Subir K. Ray, Andrew B. Lt!iter, Boston, MA.
`
`P-11
`
`

`

`97
`
`A Dominant Negative Approach For Characterization of The G·Protelns Mediating
`Histamine H, Receptor Signaling.
`Udong Wang, Meizlll Wang, Kenneth Butler, Univ of Michigan, Ann Arbor, Ml; Annette
`Gilchrist, Heidi E. Hamm, Univ of Illinois, Chicago, IL; John Del Valle. Univ of Michigan,
`Ann Arbor, Ml
`
`Background: The histamine H, receptor couples to both the adeny1ate cyclase and IP,IPKC
`signaling systems via Independent pathways. Activation of this receptor also leads to stlmula·
`lion of cen profrteration via a PKC dependent mechanism. Oespne these observations. the G·
`proteins mediating H, receptor signaling and actions have not been fully characterized. Aim:
`Utilize dominant·negatlve constructs of G-prolein a subunhs to characterize H, receptor
`mediated signaling and cell growth. Methods: HEK cells expressing the human H, receptor
`were stably transfected with mini gene plasmid constructs encoding oligonucleotide sequences
`corresponding to the carboxyl-tenninal undeca-pepllde of either Gaq, Gas, Ga12, Ga13. M1ni
`gene expression was confinned by PCA. Histamine mediated regulation of cAMP, PKC and
`cell proliferation ('H·thymldlne Incorporation) was performed using standard techniques. To
`examine c-fos transcription we translected cells with a construct containing the lucHerase
`reporter gene coupled to the serum response element (base-357 to ·276. SRHuc) ol the
`c-fos gene promoter and measured ligand stimulated lucHerase actiYJty. AesuHs: Stably trans(cid:173)
`fected cells expressing comparable receptor levels were used lor study. Histamine dose
`dependently (EC50 tO•M) stimulated cAMP generation (Emax:745% control), PKC activity
`(Emax:258% control), SRE-Luc activity (Emax:411.7't. control) and 'H·thymidine incorporalio(cid:173)
`n(Emax:195% conlrol)ln H, receptor expressing cells. Histamine stimulated cAMP generatJon
`was decreased by 56.5:t3.4% (mean:tSE.n = 4) m Gas mini gene expressing cells. The effect
`of histamine on PKC activation was inhibited by 31.5: 5.4% (mean:tSE,n- 4) and 13.2::2 5%
`(mean:tSE,n= 4;p< 0.05) lnGa12 and Gaq constructexpressing cells respectively. Histamine
`mediated stimulation ol SAE-luc and 'H·thymidine Incorporation was decreased by 20:t2%and
`40.0::2.5'4 (mean::SE,n ~ 4,p<0.05) In Gaq construct expressing cells. Histamine mediated
`SAE·luc and 'H·thym1dlne incorporation was inhibited by 58.5:!:5.6% and 36.2:t3.5%
`(mean::SE,n=4,p<0.01) In Ga12 construct expressing cells. Histamine signaling was not
`allered In cells expressing the Ga13 construct. Conclusion: The H, receptor couples to Gat2,
`and this linkage Is Important for histamine mediated cell growth. We also ldentilied Gas and
`Gaq as H, receptor targets, with the fonmer interaction being important for cAMP generation
`and the later playing a role in PKC activation and cell growth.
`
`98
`
`A Randomized, Double·BIInd, Placebo·Controlled Trial Of Subcutaneous Elanercept
`(p75 Soubte Tumor Necrosis Factor:FC Fusion Proteln)ln The Treatment Of
`Moderate To Severe Crohn's Disease.
`William J. Sandborn, Mayo Clio, Rochester, MN; Stephen 8. Hanauer, Unlv of Chicago,
`Chicago, IL; Seymour Katz, New Yorlc Univ Sch of Medicine. North Shore Univ, Long
`Island, NY; Micllaet Saldi, Greater Cincinnati Gastroenterology Assoc Inc, Cincinnati, OH,
`Douglas C. WoH, Atianta Gastroenterology Assoc. Atlanta, GA; Richard D. Baerg, Wilham J.
`Tremaine, Therese Johnson, Nancy Olehl, Alan A. Zinsmeister, Mayo Clln, Rochester, MN
`Background: Tumor necrosis factor (TNF)a plays a pivotal role in the Inflammation ol Crohn's
`disease (CO). We determined the efficacy and safety of etanercep~ a human soluble TNF
`recepto~Fc fusion protein, lor moderate to severe CO. Melhods: 43 patients with moderate
`to severe CO (CO Activi1y Index (COAl) 220-450 inclusive] were enrolled Into an 8 week study
`and randomized to twice weekly subcutaneous therapy with etanercept 25 mg or placebo. 5·
`Amlnosallcylates. antibiotics, purine anti-metabolhes, and methOtrexate were held constant
`at the pre-study dose Prednisone was held constant at the pre·study dose lor 4 weeks
`and then decreased by 5 mgtweek until discontinuation. The primary outcome was clinical
`improvement defined as a decrease In the baseline COAl score c: 70 points at week 4.
`Secondary outcomes Included clinical remission defined as a week 4 COAl score < 150, and
`clinical response and remission at week 8. Aesuks: 23 patients received etanercepl and 20
`received placebo; the cllaracterislics of the two groups were similar. AI week 4, 9123 (39%)
`of etanercepHreated patients had clinical Improvement as compared with 9120 (45'-J of
`placebo·treated patients (P = 0.763). Similarly, at week 4, 2/23 (9%) of etanercept-treated
`patients had clinical remission as compared w~h 4/20 (20%) of placebo·treated patients (p
`- 0.393). The clinical Improvement rates at week 8 were 7123 (30%) for etanercept and 61
`20 (30%) for placebo (p - 1.000). The clinical remission rates at week 8 were 3123 (13%)
`for etanercept and 5120 (25%)for placebo (p = 0.440). The frequency ol commonly occumng
`adverse events in the etanerttpt and placebo groups (% difference, 95% Cis) were: any
`adverse event 65% vs 50% (15%, ·13% to 41%); severe adverse events 4% vs 15% (·11%, •
`32% to 9%): headache 13% vs 5% (8%, ·12% to 28%); new Injection sHe reactions 13%
`vs 5% (8%, -12% to 28%); asthenia 9% vs 0% (9%, ·9% to 27%); abdominal palo 0% vs
`10% (·10%, -30% to 6%); CD related anemia 9% vs 0% (9%, ·9% to 27%): skin disorders
`9% vs 0% (9%, -9% to 27%); respectively. Conclusions: Subcutaneous etanercept at a dose
`of 25 mg twice weekly Is not an effective therapy for patients with moderate to severe CD.
`The dose of etanercept administered In this study Is that approved lor rheumatoid arthritis.
`Higher doses or more trequent dosing may be required to attain a response in patients with
`active CO. The frequency of adverse events was not signifiCantly different in the two groups.
`
`acid (1.5 ml, 0.6%). The number ol abdominal contractions determined the level of colonic
`stimulation in response to Innocuous CAD (10 mmHg, 10 min.). One hour prior to testing,
`animals received eltller a single oral dose of TAK-637 (0.3 3 mg/kg) or a melhylcellulose
`vehicle. Untruted guinea-pigs served as controls. AesuHs: We found that In vehicle-treated
`mimals, partial restraint stress or lntracolonlc acetic acid Induced an ~~rated VISCeromotor
`response to Innocuous CAD (partial restraint stress c 23.3:!:3.4; acet•c aCid • 24.5:t3.2) com(cid:173)
`pared to untreated controls• 9.5:t1.4 (p < 0.01). In partial restraint stressed animals,
`pretreatment with TAK-637 caused a significant Inhibition in the number of abdominal contrac(cid:173)
`tions In response to CAD (6.0:2.0. p< 0.001) which reached a maximum at a dose of 3
`~. The same dose of TAK-637 also abolished colonic hypersensitivity induced by intraco(cid:173)
`lonlc acetic actd and CAD Induced a visceromotor response resembling that in controls
`(9.3±1.4, p<0.001). Summary: A selective NK, antagonist TAK-637 inhiMed colonic hyper·
`sensitivity Induced by partial restraint stress or lntracoloolc administration of acetic acid.
`Conclusion: Our results demonstrate that NK,·receptor mediated mechanisms are Involved in
`colonic hypersensitivity and we speculate that TAK-637 may be a noveltherapeutJc approacll
`for the treatment of patients with Irritable bowtl syndrome.
`
`Dltferantlal Signaling by Muscarinic m3 and m2 Receptors Determines Sustained
`Myosin Light Chain (MLC) Phosphorylation and Smooth Muscle Contraction.
`Karnam S. Murthy, Huiping Zhou, Gabriel M. Makhlouf, Medical Coil of VIrginia, VCU,
`Richmond. VA
`BACKGROUND. Initial smooth muscle contraction Induced by muscartnlc agonists is mediated
`by m3 but not m2 receptors. The roles of m3 and m2 receptors in sustained contraction
`have not been explored. AIM. To ldenti1y the signaling pathways Initiated by m3 and m2
`receptors and their roles in MLC10 phosphorylation and sustained contraction. METHODS. (a)
`MLC kinase (MLCK) and MLC;oo phosphorylation, (b) Rho kinase, phosphoHpase 0 (Pl.O)and
`p21·activated kinase (PAK) activitles, and (c) sustained muscle contraction were measured
`In freshly dispersed or cunured Intestinal muscle cells. AESUL TS. Exposure of muscle cells
`to acetylcholine (ACh) for 10 min. stimulated MLC, and MLCK phosphorylation. activated
`Aho·kinase. PAK. and PLO, and Induced sustained muscle contraction. MLCK phosphorylation
`was abolished by the m2 antagonist, methoctramine, and by PAK antibody, but was not
`affected by the m3 antagonist, 4-0AMP, or by AhoA antibody. PAK activity was abolished by
`the m2 antagonist, and In cells co-expressing dominant negattve Cde42 and Aac1. The pattern
`Implied that MLCK phosphorylation was mediated by m2·dependent, sequential activation of
`Cde42/Rac1 and PAK. In contras~ MLC, phosphorylation. and Rho kinase and PLO activ~ies
`were abolished In cells express1ng dominant negative AhoA. Rho kinase activity was blocked
`by m3 but not m2 antagonists The pattern implied that MLC, phosphorylabon was mediated
`by m3-dependenl sequential activation of Rho kinase and PLO. Phosphatidic acid, the prtmary
`product of PlO, Is the main source of sustained diacylglycerol formation and PKC activi1y In
`smooth muscle. Inhibition of PKC activity wHh blsindolylmalelmlde or lnhibttlon of Rho kinase
`act.iYity with Y-27632. aboHshed ACh·induced sustained contractlon. Our recent studies llave
`shown that sustained MLC, phosphorylation and contraction Induced by a dtfferent agonist
`(CCK-8) are abolished by the PKC inhib~or, calphostin C. A 1HOa PKC·activated protein
`(CPI·17) that lnhlbtts MLC phospllatase could serve as the link between PKC and MLC,.
`phosphorylation. CONCLUSION. Sustained MLC, phosphorylation and contraction Induced
`by muscarinic agonists are mediated by m3 receptors via a slgnal1ng pathway involving
`sequential activat1on of AhoA. Rho kinase, PLO. and PKC. Sustained MLC, phosphorylation
`Is not mediated by MLCK; the latter Is lnhlbtted by phosphorylation via an m2-dependent
`pathway Involving sequential act1vat1on of Cdc42/Aac1 and PAK.
`
`IGFBP·5 Stimulates Growth ot Human Intestinal Smooth Muscle Independently ol
`IGF·I by Al:tlvatlon of p38· and p42/44·MAP Klnases.
`John F. Kuemmerle, Medical Coil of Virginia, VCU. Richmond. VA
`BACKGROUND: We and others have shown that human intestinal smooth muscle cells secrete
`IGF-1 and IGFBP·S. Their secrelion Is highest during the in~ial prol~erative phase of growth.
`IGF·I activates distinct PI 3·klnase and p42/44 MAP kinase pathways that stimulate both
`growth and IGFBP-5 secrellon. The recent dlsovery of a specHic IGFBP-5 receptor serine
`kinase raised the possibility that IGFBP-5 can independently sbmulate growth and IGF-1
`secrelion. AIM: To Identify the signaling pathways initiated by IGFBP·5 and detennine their
`effects on growth and IGF-1 secretion. METHODS: Muscle cells were isolated from the circular
`layer of normal human intestine, cultured In DMEM + 10% FCS and used after confluence in
`first passage when endOQ!nous IGF-1 and IGFBP-5 levels were lowest Muscle cells were
`rendered quiescent by 24 h Incubation in serum-free medium. Growth was measured by
`('H]thymidine Incorporation. IGF-1 secretion was measured by radioimmunoassay after acid·
`ethanol extraction to remove IGF binding proteins. Phosphorylation ol p38 MAP kinase (Thr180/
`Tyr182), p42/44 MAP kinase (Thr202/Tyr204), and MAP kinase kinase 316 (MKK3/6)(Ser1891
`Ser207) was measured by Western blot analysis using phosphophorylation state-specific
`antbodies. RESULTS: All experiments were done In the presence of the IGF-1 receptor antago(cid:173)
`nist, IGF analog, so as to block Indirect effects ot IGFBP·S mediated via the IGH receptor.
`Incubation of quiescent muscle cells for 15 min with 50 oM IGFBP-5 elicited prompt phosphory(cid:173)
`lation of MKK3/6, the p38-speclflc MAP kinase kinase (120±20% above basal), and p38 MAP
`kinase (310:!:60% above basal). IGFBP·S also caused phosphorylation of p42/44 MAP kinase
`( 190! 15% above basal).lncubation of muscle cells for 24 h with IGFBP·S increased ('H]Ihyml·
`dine incorporation In a concentration-dependent fashion (145:t9% with 50 nM IGFBP-5).
`(' H]thymidine Incorporation elictted by IGFBP·5 was lnhibtted 69:t5% by the p38 MAP kinase
`lnhibttor, SB203580 (10 iM). and 40±5% by the p44/42·specific MAP kinase kinase (MKK1
`or MEK1) Inhibitor, P098059 (10 iM).IGFBP-5 (50 nM) Increased IGF-1 secretion by 61 ±12%
`above basal. CONCLUSIONS: Activation of the IGFBP-5 receptor serine kinase (a) stimulates
`growth via p38-dependent and p«/42 MAP killasHependent pathways, and (b) stimulates
`IGF-1 secretion. Reciprocal stimulatory pathways link IGF-1 and IGFBP-5 secretion that reinforce
`their Individual abilities to promote growth of human intestinal smooth muscle.
`
`A-20
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