{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:22:00Z","timestamp":1778286120006,"version":"3.51.4"},"reference-count":42,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2002,1,1]],"date-time":"2002-01-01T00:00:00Z","timestamp":1009843200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Infect Immun"],"published-print":{"date-parts":[[2002,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Bromelain, a mixture of cysteine proteases from pineapple stems, blocks signaling by the mitogen-activated protein (MAP) kinases extracellular regulated kinase 1 (ERK-1) and ERK-2, inhibits inflammation, and protects against enterotoxigenic<jats:italic>Escherichia coli<\/jats:italic>infection. In this study, we examined the effect of bromelain on<jats:italic>Salmonella enterica<\/jats:italic>serovar Typhimurium infection, since an important feature of its pathogenesis is its ability to induce activation of ERK-1 and ERK-2, which leads to internalization of bacteria and induction of inflammatory responses. Our results show that bromelain dose dependently blocks serovar Typhimurium-induced ERK-1, ERK-2, and c-Jun NH<jats:sub>2<\/jats:sub>-terminal kinase (JNK) activation in Caco-2 cells. Bromelain also blocked signaling induced by carbachol and anisomycin, pharmacological MAP kinase agonists. Despite bromelain inhibition of serovar Typhimurium-induced MAP kinase signaling, it did not prevent subsequent invasion of the Caco-2 cells by serovar Typhimurium or alter serovar Typhimurium -induced decreases in resistance across Caco-2 monolayers. Surprisingly, bromelain also did not block serovar Typhimurium-induced interleukin-8 (IL-8) secretion but synergized with serovar Typhimurium to enhance IL-8 production. We also found that serovar Typhimurium does not induce ERK phosphorylation in Caco-2 cells in the absence of serum but that serovar Typhimurium-induced invasion and decreases in monolayer resistance are unaffected. Collectively, these data indicate that serovar Typhimurium-induced invasion of Caco-2 cells, changes in the resistance of epithelial cell monolayers, and IL-8 production can occur independently of the ERK and JNK signaling pathways. Data also confirm that bromelain is a novel inhibitor of MAP kinase signaling pathways and suggest a novel role for proteases as inhibitors of signal transduction pathways in intestinal epithelial cells.<\/jats:p>","DOI":"10.1128\/iai.70.1.86-95.2002","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T10:03:40Z","timestamp":1027764220000},"page":"86-95","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":39,"title":["Proteolytic Inhibition of<i>Salmonella enterica<\/i>Serovar Typhimurium-Induced Activation of the Mitogen-Activated Protein Kinases ERK and JNK in Cultured Human Intestinal Cells"],"prefix":"10.1128","volume":"70","author":[{"given":"Tracey L.","family":"Mynott","sequence":"first","affiliation":[{"name":"Center for Molecular Microbiology and Infection, Imperial College of Science, Technology and Medicine, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ben","family":"Crossett","sequence":"additional","affiliation":[{"name":"Center for Molecular Microbiology and Infection, Imperial College of Science, Technology and Medicine, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. Radhika","family":"Prathalingam","sequence":"additional","affiliation":[{"name":"Center for Molecular Microbiology and Infection, Imperial College of Science, Technology and Medicine, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"G631","volume":"277","year":"1999","unstructured":"Aliaga, J. C., C. Deschenes, J. F. Beaulieu, E. L. Calvo, and N. Rivard. 1999. Requirement of the MAP kinase cascade for cell cycle progression and differentiation of human intestinal cells. Am. J. Physiol.277:G631\u2013G641.","journal-title":"Am. J. Physiol."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.50.29710"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/gut.43.2.196"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5295.2115"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1159\/000227219"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.1999.00797.x"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1006\/cimm.2001.1793"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/162.5.1096"},{"key":"e_1_3_2_10_2","first-page":"219","volume":"12","year":"1996","unstructured":"Galan, J. E., and J. B. Bliska. 1996. Cross-talk between bacterial pathogens and their host cells. Annu. Rev. Cell Dev. Biol.12:219\u2013253.","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI1339"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.64.1.135-145.1996"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.23.1.140-145.1979"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81442-7"},{"key":"e_1_3_2_15_2","doi-asserted-by":"crossref","first-page":"5550","DOI":"10.4049\/jimmunol.159.11.5550","volume":"159","year":"1997","unstructured":"Hobbie, S., L.-M. Chen, R. J. Davis, and J. E. Galan. 1997. Involvement of mitogen-activated protein kinase pathways in the nuclear responses and cytokine production induced by Salmonella typhimurium in cultured intestinal epithelial cells. J. Immunol.159:5550\u20135559.","journal-title":"J. Immunol."},{"key":"e_1_3_2_16_2","first-page":"1199","volume":"78","year":"1993","unstructured":"Izquierdo, M., S. J. Leevers, C. J. Marshall, and D. Cantrell. 1993. p21ras couples the T cell antigen receptor to extra signal regulated kinase in T cells. J. Exp. Med.78:1199\u20131208.","journal-title":"J. Exp. Med."},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.2184"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117676"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.1.178"},{"key":"e_1_3_2_20_2","first-page":"680","volume":"132","year":"2000","unstructured":"Kane, S., and M. J. Goldberg. 2000. Use of bromelain for mild ulcerative colitis. Ann. Intern. Med.132:680.","journal-title":"Ann. Intern. Med."},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.42.27111"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3370275"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-199300461-00033"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.67.2.688-693.1999"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.123.4.895"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1006\/mpat.1994.1086"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(97)80059-2"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.59.10.3708-3714.1991"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(97)70093-3"},{"key":"e_1_3_2_30_2","doi-asserted-by":"crossref","first-page":"2568","DOI":"10.4049\/jimmunol.163.5.2568","volume":"163","year":"1999","unstructured":"Mynott, T. L., A. Ladhams, P. Scarmato, and C. R. Engwerda. 1999. Bromelain, from pineapple stems, proteolytically blocks activation of extracellular regulated kinase-2 in T cells. J. Immunol.163:2568\u20132575.","journal-title":"J. Immunol."},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1136\/gut.38.1.28"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3010727"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90070-7"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.67.3.1011-1017.1999"},{"key":"e_1_3_2_35_2","doi-asserted-by":"crossref","first-page":"4924","DOI":"10.4049\/jimmunol.163.9.4924","volume":"163","year":"1999","unstructured":"Procyk, K. J., M. R. Rippo, R. Testi, F. Hoffmann, P. J. Parker, and M. Baccarini. 1999. Distinct mechanisms target stress and extracellular signal-activated kinase 1 and Jun N-terminal kinase during infection of macrophages with Salmonella.J. Immunol.163:4924\u20134930.","journal-title":"J. Immunol."},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.60.6.2211-2217.1992"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.62.11.4969-4974.1994"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1998.274.6.C1573"},{"key":"e_1_3_2_39_2","doi-asserted-by":"crossref","first-page":"5681","DOI":"10.4049\/jimmunol.161.10.5681","volume":"161","year":"1998","unstructured":"Scherle, P. A., E. A. Jones, M. F. Favata, A. J. Daulerio, M. B. Covington, S. A. Nurnberg, R. L. Magolda, and J. M. Trzaskos. 1998. Inhibition of MAP kinase kinase prevents cytokine and prostaglandin E2 production in lipopolysaccharide-stimulated monocytes. J. Immunol.161:5681\u20135686.","journal-title":"J. Immunol."},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.66.3.1106-1112.1998"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3310863"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2000.01892.x"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI7545"}],"container-title":["Infection and Immunity"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/IAI.70.1.86-95.2002","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/IAI.70.1.86-95.2002","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,23]],"date-time":"2023-04-23T15:34:58Z","timestamp":1682264098000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/IAI.70.1.86-95.2002"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,1]]},"references-count":42,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2002,1]]}},"alternative-id":["10.1128\/IAI.70.1.86-95.2002"],"URL":"https:\/\/doi.org\/10.1128\/iai.70.1.86-95.2002","relation":{},"ISSN":["0019-9567","1098-5522"],"issn-type":[{"value":"0019-9567","type":"print"},{"value":"1098-5522","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,1]]},"assertion":[{"value":"2001-06-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2001-10-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2002-01-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}