Cyclosporin A and FK506 Inhibit IL-12p40 Production through the Calmodulin/Calmodulin-dependent Protein Kinase-activated Phosphoinositide 3-Kinase in Lipopolysaccharide-stimulated Human Monocytic Cells

Pourquoi ce travail est-il dans la base ?

Une base qui oublie comment elle a trouvé un travail ne peut pas être vérifiée. Voici les voies qui ont admis celui-ci.

Dossier post-publication

Nature

Retraction

Motif

Investigation by Company/Institution;Manipulation of Images;Notice - Limited or No Information;

Date

1/2/2012 0:00

Signalé par OpenAlex ?

Oui

Source : Retraction Watch, jointe par DOI. OpenAlex consigne la rétractation dans is_retracted, un booléen sur un espace d'états à au moins quatre valeurs ; il ne peut donc exprimer ni une expression de préoccupation, ni une correction, ni un rétablissement, et les rapporte comme false, ce qui se lit comme « rien à signaler ».

Résumé

Cyclosporine-A (CyA) and FK506 are potent immunosuppressive agents because of their ability to suppress the production of Th1 cytokines including interleukin (IL)-12. However, the mechanisms underlying the inhibitory effects of CyA and FK506 on the production of IL-12p40, a critical component of IL-12, remain unknown. Both CyA and FK506 are potent inhibitors of calcineurin in the calcium signaling pathway. Interestingly, calcium and phosphoinositide 3-kinase (PI3K) signaling pathways have been shown to negatively regulate lipopolysaccharide (LPS)-induced murine IL-12p40 production. Contrary to these observations, we show that LPS-induced IL-12p40 production in human monocytic cells is positively regulated by the calcium pathway and in particular by calmodulin-(CaM) and CaM-dependent protein kinase-II (CaMK-II)-activated PI3K. Furthermore, LPS-induced IL-12p40 production was regulated by the p110α catalytic subunit of PI3K. Moreover, LPS induced IL-12p40 production through the CaM/CaMK-II-activated NFκB and AP-1 transcription factors. LPS-induced IL-12p40 production is known to be regulated by the c-Jun N-terminal kinase (JNK) pathway. Importantly, both CyA and FK506 down-regulated LPS-induced IL-12p40 transcription by inhibiting CaM/CaMK-II-activated PI3K and their downstream transcription factors NFκB and AP-1 independent of the JNK pathway. Cyclosporine-A (CyA) and FK506 are potent immunosuppressive agents because of their ability to suppress the production of Th1 cytokines including interleukin (IL)-12. However, the mechanisms underlying the inhibitory effects of CyA and FK506 on the production of IL-12p40, a critical component of IL-12, remain unknown. Both CyA and FK506 are potent inhibitors of calcineurin in the calcium signaling pathway. Interestingly, calcium and phosphoinositide 3-kinase (PI3K) signaling pathways have been shown to negatively regulate lipopolysaccharide (LPS)-induced murine IL-12p40 production. Contrary to these observations, we show that LPS-induced IL-12p40 production in human monocytic cells is positively regulated by the calcium pathway and in particular by calmodulin-(CaM) and CaM-dependent protein kinase-II (CaMK-II)-activated PI3K. Furthermore, LPS-induced IL-12p40 production was regulated by the p110α catalytic subunit of PI3K. Moreover, LPS induced IL-12p40 production through the CaM/CaMK-II-activated NFκB and AP-1 transcription factors. LPS-induced IL-12p40 production is known to be regulated by the c-Jun N-terminal kinase (JNK) pathway. Importantly, both CyA and FK506 down-regulated LPS-induced IL-12p40 transcription by inhibiting CaM/CaMK-II-activated PI3K and their downstream transcription factors NFκB and AP-1 independent of the JNK pathway. Cyclosporin A and FK506 inhibit IL-12p40 production through the calmodulin/calmodulin-dependent protein kinase-activated phosphoinositide 3-kinase in lipopolysaccharide-stimulated human monocytic cells.Journal of Biological ChemistryVol. 287Issue 1PreviewVOLUME 282 (2007) PAGES 13351–13362 Full-Text PDF Open Access Cyclosporine (CyA) 7The abbreviations used are: CyA, cyclosporine; CaM, calmodulin; CaMK-II, calmodulin-dependent protein kinase-II; DC, dendritic cell; ER, endoplasmic reticulum; JNK, c-Jun N-terminal kinase; PI3K, phosphoinositide 3-kinase; LPS, lipopolysaccharide; PBMC, peripheral blood mononuclear cell; IMDM, Iscove’s modified Dulbecco’s medium; FBS, fetal bovine serum; ELISA, enzyme-linked immunosorbent assay; Ab, antibody; mAb, monoclonal antibody; RT, reverse transcription; NFAT, nuclear factor of activated T cells; siRNA, small interfering RNA; PMA, phorbol 12-myristate 13-acetate. and FK506 (Tacrolimus) are immunosuppressive agents and have been widely used in a variety of disease conditions such as clinical post-organ transplantation and autoimmune diseases (1Jiang H. Wynn C. Pan F. Ebbs A. Erickson L.M. Kobayashi M. Transplantation. 2002; 73: 1808-1817Crossref PubMed Scopus (50) Google Scholar, 2Hariharan S. Johnson C.P. Bresnahan B.A. Taranto S.E. McIntosh M.J. Stablein D. N. Engl. J. Med. 2000; 342: 605-612Crossref PubMed Scopus (1629) Google Scholar). CyA is a cyclic polypeptide produced as a fungal metabolite and consists of 11 amino acids, whereas FK506 is a macrolide lactone (2Hariharan S. Johnson C.P. Bresnahan B.A. Taranto S.E. McIntosh M.J. Stablein D. N. Engl. J. Med. 2000; 342: 605-612Crossref PubMed Scopus (1629) Google Scholar). CyA and FK506 bind to cyclophilin A and the 12-kDa FK506-binding protein, FKBP12, respectively, and suppress activation of NFAT in T cells (3Kiani A. Rao A. Aramburu J. Immunity. 2000; 12: 359-372Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar, 4Crabtree G.R. Cell. 1999; 96: 611-614Abstract Full Text Full Text PDF PubMed Scopus (669) Google Scholar). CyA and FK506 are potent inhibitors of Ca2+-dependent T cell activation, and the CyA-cyclophilin A and FK506-FKBP12 complexes bind to the same target, calcineurin (3Kiani A. Rao A. Aramburu J. Immunity. 2000; 12: 359-372Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar, 4Crabtree G.R. Cell. 1999; 96: 611-614Abstract Full Text Full Text PDF PubMed Scopus (669) Google Scholar, 5Schreiber S.L. Crabtree G.R. Immunol. Today. 1992; 13: 136-142Abstract Full Text PDF PubMed Scopus (1968) Google Scholar), thereby inhibiting the T cell antigen receptor-mediated signal transduction pathway. FK506 and CyA modulate the biological functions of T cells, B cells, macrophages, and dendritic cells (DCs) (5Schreiber S.L. Crabtree G.R. Immunol. Today. 1992; 13: 136-142Abstract Full Text PDF PubMed Scopus (1968) Google Scholar, 6Woltman A.M. de Fijter J.W. Kamerling S.W. Paul L.C. Daha M.R. van K.C. Eur. J. Immunol. 2000; 30: 1807-1812Crossref PubMed Scopus (238) Google Scholar, 7Sauma D. Fierro A. Mora J.R. Lennon-Dumenil A.M. Bono M.R. Rosemblatt M. Morales J. Transplant. Proc. 2003; 35: 2515-2517Crossref PubMed Scopus (41) Google Scholar, 8Tajima K. Amakawa R. Ito T. Miyaji M. Takebayashi M. Fukuhara S. Immunology. 2003; 108: 321-328Crossref PubMed Scopus (76) Google Scholar, 9Wasowska B.A. Zheng X.X. Strom T.B. Kupieck-Weglinski J.W. Transplantation. 2001; 71: 1179-1183Crossref PubMed Scopus (30) Google Scholar) and have been shown to inhibit Th1 responses by interfering with cytokine production including IL-12 by murine DCs (1Jiang H. Wynn C. Pan F. Ebbs A. Erickson L.M. Kobayashi M. Transplantation. 2002; 73: 1808-1817Crossref PubMed Scopus (50) Google Scholar, 6Woltman A.M. de Fijter J.W. Kamerling S.W. Paul L.C. Daha M.R. van K.C. Eur. J. Immunol. 2000; 30: 1807-1812Crossref PubMed Scopus (238) Google Scholar, 7Sauma D. Fierro A. Mora J.R. Lennon-Dumenil A.M. Bono M.R. Rosemblatt M. Morales J. Transplant. Proc. 2003; 35: 2515-2517Crossref PubMed Scopus (41) Google Scholar, 8Tajima K. Amakawa R. Ito T. Miyaji M. Takebayashi M. Fukuhara S. Immunology. 2003; 108: 321-328Crossref PubMed Scopus (76) Google Scholar, 9Wasowska B.A. Zheng X.X. Strom T.B. Kupieck-Weglinski J.W. Transplantation. 2001; 71: 1179-1183Crossref PubMed Scopus (30) Google Scholar). IL-12 is produced by monocytic cells, DCs, B cells, and other accessory cells and plays a key role in the development of Th1 responses (10Ma X. Trinchieri G. Adv. Immunol. 2001; 79: 55-92Crossref PubMed Scopus (172) Google Scholar, 11Scott P. Trinchieri G. Semin. Immunol. 1997; 9: 285-291Crossref PubMed Scopus (74) Google Scholar, 12Biron C.A. Gazzinelli R.T. Curr. Opin. Immunol. 1995; 7: 485-496Crossref PubMed Scopus (218) Google Scholar, 13Cooper A.M. Kipnis A. Turner J. Magram J. Ferrante J. Orme I.M. J. Immunol. 2002; 168: 1322-1327Crossref PubMed Scopus (265) Google Scholar, 14Gately M.K. Desai B.B. Wolitzky A.G. Quinn P.M. Dwyer C.M. Podlaski F.J. Familletti P.C. Sinigaglia F. Chizonnite R. Gubler U. J. Immunol. 1991; 147: 874-882PubMed Google Scholar). It is a potent inducer of interferon-γ either alone or in synergy with other inducers and causes proliferation of T and NK cells and lymphokine-activated killer cells (11Scott P. Trinchieri G. Semin. Immunol. 1997; 9: 285-291Crossref PubMed Scopus (74) Google Scholar, 12Biron C.A. Gazzinelli R.T. Curr. Opin. Immunol. 1995; 7: 485-496Crossref PubMed Scopus (218) Google Scholar, 13Cooper A.M. Kipnis A. Turner J. Magram J. Ferrante J. Orme I.M. J. Immunol. 2002; 168: 1322-1327Crossref PubMed Scopus (265) Google Scholar, 14Gately M.K. Desai B.B. Wolitzky A.G. Quinn P.M. Dwyer C.M. Podlaski F.J. Familletti P.C. Sinigaglia F. Chizonnite R. Gubler U. J. Immunol. 1991; 147: 874-882PubMed Google Scholar). IL-12 is a heterodimeric 70-kDa protein composed of a disulfide linked 40-kDa and 35-kDa subunits (15Gubler U. Chua A.O. Schoenhaut D.S. Dwyer C.M. McComas W. Motyka R. Nabavi N. Wolitzky A.G. Quinn P.M. Familletti P.C. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 4143-4147Crossref PubMed Scopus (565) Google Scholar, 16Aste-Amezaga M. Ma X. Sartori A. Trinchieri G. J. Immunol. 1998; 160: 5936-5944PubMed Google Scholar). Although the IL-12p40 subunit is secreted in excess over IL-12p70, only the heterodimer is biologically active. Many cell types, including those that are not known to produce IL-12, express mRNA-encoding IL-12p35. However, mRNA-encoding IL-12p40 seems to be restricted to cells that produce the biologically active IL-12 (15Gubler U. Chua A.O. Schoenhaut D.S. Dwyer C.M. McComas W. Motyka R. Nabavi N. Wolitzky A.G. Quinn P.M. Familletti P.C. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 4143-4147Crossref PubMed Scopus (565) Google Scholar, 16Aste-Amezaga M. Ma X. Sartori A. Trinchieri G. J. Immunol. 1998; 160: 5936-5944PubMed Google Scholar). Therefore, IL-12p40 expression is generally considered as an indicator of IL-12p70 production. Moreover, the IL-12p40 subunit is also shared by another Th1 cytokine, IL-23, which makes it a highly significant cytokine of Th1 responses de M.R. Immunol. PubMed Scopus Google Scholar). is on the role of signaling that regulate IL-12p40 in human monocytic cells LPS LPS-induced cell signaling activation of and protein including and the protein J. M. J. Immunol. 1999; Google Scholar, J. PubMed Scopus Google Scholar, W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar, W. K. S. A. J. Immunol. PubMed Scopus Google Scholar). and W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar, M. K. T. K. J. T. M. J. Immunol. 2003; PubMed Scopus Google Scholar) have the of kinase (JNK) in IL-12p40 production in human monocytic transcription factors including interferon-γ and transcription and their complexes have been to regulate IL-12p40 transcription in murine and human monocytic cells W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar, I.M. C. A. Ma X. Trinchieri G. K. J. Immunol. 2000; PubMed Scopus Google Scholar, S.E. S. Cell. 1997; PubMed Scopus Google Scholar, X. M. G. Trinchieri G. J. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. Immunol. 2001; PubMed Scopus Google Scholar, P. Magram J. Cell. 1995; PubMed Google Scholar, C. Rao K. H. K. F. C. S. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). by which CyA and FK506 inhibit IL-12p40 production in monocytic cells unknown. both FK506 and CyA are potent inhibitors of calcineurin (3Kiani A. Rao A. Aramburu J. Immunity. 2000; 12: 359-372Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar, 4Crabtree G.R. Cell. 1999; 96: 611-614Abstract Full Text Full Text PDF PubMed Scopus (669) Google Scholar), we that these agents inhibit IL-12p40 production through with calcium However, have the role of calcium and the phosphoinositide 3-kinase (PI3K) signaling in LPS-induced IL-12p40 production in murine and DCs C.M. Trinchieri G. Ma X. J. Immunol. 2001; PubMed Scopus Google Scholar, P. J. Med. 1998; PubMed Scopus Google Scholar, R. J. Med. 1997; PubMed Scopus Google Scholar, T. S. Immunol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, T. M. T. S. T. T. T. S. Immunol. 2002; PubMed Scopus Google Scholar, M. N. J. J. Immunol. 2003; PubMed Scopus Google Scholar, R. J. Immunol. PubMed Scopus Google Scholar, M. J. Immunol. PubMed Scopus Google Scholar). and in to the of murine IL-12p40 that LPS-induced IL-12p40 production is positively regulated by the PI3K as as the calcium signaling in particular and the calmodulin-dependent protein kinase-II Furthermore, both CyA and FK506 LPS-induced IL-12p40 production by inhibiting the activation of and and their downstream NFκB and AP-1 transcription factors the JNK pathway. of and of blood as W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar). by over by by of T and B cells with and T cells and B cells as by human cell was the in with and IL-12p40 was by that as W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar). IL-12p40 was by a and a and respectively, was used a of was used as a of the IL-12p40 was and was as a and W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar). was reverse by murine reverse of to of IL-12p40 and their as W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar). was with and IL-12p40 on in of calcium by as S. K. A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). with FK506 and CyA by with and in A was by an of B A FBS, cells in the and the of LPS by a with and used as of PI3K, p110α PI3K, JNK, CaMK-II, and NFAT PI3K, or protein the and with their by as W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar). of of to by and the of the as W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar). in AP-1 NFκB on IL-12p40 to was by W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar). by the of was by as W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar, W. W. K. S. D. M. F. A. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). of the and of the in of was with of in of to of complexes to the cell in cells with LPS another by of and by and by W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar). of PI3K with PI3K and as the cells with LPS and PI3K. of IL-12p40 cells in and with A the in B Both A and B the inhibitors and have been W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar). with either AP-1 or NFκB W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar), and the complexes to of NFκB and AP-1 the and to the NFκB and AP-1 in the IL-12p40 used as as W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar). was and to by are as S.E. FK506 and CyA LPS-induced IL-12p40 by a in of human and cells induced expression of IL-12p40 of cells with either CyA or FK506 to with LPS IL-12p40 expression as by and in both and FK506 and CyA their biological effects by inhibiting the signaling pathway (3Kiani A. Rao A. Aramburu J. Immunity. 2000; 12: 359-372Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar, 4Crabtree G.R. Cell. 1999; 96: 611-614Abstract Full Text Full Text PDF PubMed Scopus (669) Google Scholar), we the role of calcium signaling in LPS-induced IL-12p40 production. of and cells with LPS the of calcium and respectively, that was of cells with FK506 and CyA LPS-induced in calcium in both a of to the of and cells a of to the of in a that FK506 and CyA are biologically cells with these agents to with another by of expression by is in the that is by of cells with either CyA or FK506 and of the which was by of cells with FK506 or CyA a LPS-induced in calcium and IL-12p40 cells with to LPS LPS-induced IL-12p40 production in both cell as by and of IL-12p40 production by FK506 and CyA is in and FK506 and CyA inhibit LPS-induced in the of calcium in and with of FK506 and CyA and with by LPS of calcium by the biological of FK506 and CyA was by their on expression in T T cells with FK506 and CyA and with expression by protein and with cells and with to by LPS another IL-12p40 production in the was by shown are a of IL-12p40 expression is regulated by and PI3K and cells with inhibitors the to with LPS by IL-12p40 expression by as an shown are of independent LPS-induced IL-12p40 the role of calcium we used inhibitors of the calcium signaling pathway. in calcium by that or calcium in the or of calcium in in the endoplasmic M.J. Cell. 2003; PubMed Scopus Google Scholar, A.M. G. K. F. M.J. J. PubMed Scopus Google Scholar). role of receptor-mediated of was by R. A. J. PubMed Scopus Google Scholar). calcium the IL-12p40 we an of the which calcium the by M.J. C.M. J. 2002; PubMed Scopus Google Scholar). of cells with either or LPS-induced IL-12p40 production in both cell as by and It be that to the effects of and that receptor-mediated as as the the be in LPS-induced IL-12p40 CaM, a calcium is in both and nuclear downstream including protein and G. PubMed Scopus Google Scholar, J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the role of CaM, we used a S. K. A. J. Full Text Full Text PDF PubMed Scopus Google Scholar, A. A. Cell. 2003; PubMed Scopus Google Scholar). LPS-induced IL-12p40 production in both cell as by and of is the calmodulin-dependent protein kinase which a the role of we the role of by the H. 1995; PubMed Scopus Google Scholar, 2003; PubMed Scopus Google Scholar), which LPS-induced IL-12p40 production in both cell as by and also that LPS induced was by and in both cell S. K. A. J. Full Text Full Text PDF PubMed Scopus Google and p110α of PI3K LPS-induced IL-12p40 PI3K pathway negatively IL-12p40 expression in murine DCs and monocytic cells T. S. Immunol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, T. M. T. S. T. T. T. S. Immunol. 2002; PubMed Scopus Google Scholar, M. N. J. J. Immunol. 2003; PubMed Scopus Google Scholar, R. J. Immunol. PubMed Scopus Google Scholar, M. J. Immunol. PubMed Scopus Google Scholar). Therefore, it was of to PI3K human IL-12p40 production in a to the calcium pathway. Therefore, we that LPS induced of a downstream PI3K, and in both and cells Interestingly, LPS-induced IL-12p40 expression in both cell and PI3K are of a subunit or other and a or catalytic K. J. R. P.C. R. 2001; PubMed Scopus Google Scholar, D. R. C. C. 1999; PubMed Scopus Google Scholar, U. J. A. J. 1998; PubMed Scopus Google Scholar). we the role of the p110α by cells in the p110α A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). with a the p110α subunit cells of the PI3K p110α expression the expression of or that of and A. J. Full Text Full Text PDF PubMed Scopus Google and not with the of the p110α and A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). the of the PI3K p110α cells and cells and with LPS and IL-12p40 show that IL-12p40 production was in cells with with the a key role p110α of PI3K in LPS-induced IL-12p40 production. role of subunit of PI3K was by cells with or a with LPS-induced and IL-12p40 expression as by and FK506 and CyA LPS-induced IL-12p40 by CaM/CaMK-II-activated PI3K of the JNK have a key role JNK in LPS-induced IL-12p40 production W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar). PI3K is in signaling and been shown to regulate and JNK protein C. B.A. S. R. K. K. 1999; PubMed Scopus Google Scholar, J. J. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), we activation of PI3K, and JNK by LPS pathways in IL-12p40 was by cells with of inhibitors signaling by LPS and of and JNK and CyA of on JNK in cells and that LPS-induced IL-12p40 production is regulated by PI3K activated by and the JNK independent of the Moreover, CyA and FK506 LPS-induced IL-12p40 production through the of pathways calcium and PI3K the JNK pathway A and FK506 and CyA LPS-induced IL-12p40 by NFκB and AP-1 through the of and PI3K have shown that LPS-induced IL-12p40 production is regulated by JNK through the activation of NFκB and AP-1 W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar). LPS-induced IL-12p40 production is regulated by CaM/CaMK-II-activated NFκB we by cells with a of IL-12p40 linked with the LPS-induced that with the to induced significant with the cells with the whereas with the with NFκB in the of the with AP-1 and NFκB an of LPS However, both AP-1 and NFκB LPS-induced was that both AP-1 and NFκB regulate LPS-induced IL-12p40 production and that either or the other are to IL-12p40 been shown to as a of kinase activation in to cell K. S. A. T. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). regulated LPS-induced IL-12p40 expression through NFκB activation, cells with the IL-12p40 and the with inhibitors of the calcium and PI3K pathways CyA, and to LPS by of these agents the LPS-induced in cells with the to the and that and of LPS-induced IL-12p40 transcription in human monocytic cells and activation of NFκB FK506 and CyA of NFκB and AP-1 to in the IL-12p40 through the and PI3K that NFκB and AP-1 regulate LPS-induced IL-12p40 transcription W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar). LPS induced significant of NFκB and of NFκB and AP-1 was by with and and by with and and and AP-1 A and of NFκB and AP-1 to their in the IL-12p40 was regulated by PI3K, cells with inhibitors of the calcium and PI3K signaling pathways with CyA, and the of NFκB and AP-1 to their in cells A and that LPS-induced IL-12p40 transcription is regulated by as as PI3K through NFκB and AP-1 Moreover, CyA and FK506 IL-12p40 transcription by inhibiting AP-1 and NFκB CyA and FK506 are potent inhibitors of signaling and their biological effects through calcineurin (3Kiani A. Rao A. Aramburu J. Immunity. 2000; 12: 359-372Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar, 4Crabtree G.R. Cell. 1999; 96: 611-614Abstract Full Text Full Text PDF PubMed Scopus (669) Google Scholar). PI3K and calcium pathways shown to negatively regulate LPS-induced IL-12p40 expression in murine and DCs T. S. Immunol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, T. M. T. S. T. T. T. S. Immunol. 2002; PubMed Scopus Google Scholar, M. N. J. J. Immunol. 2003; PubMed Scopus Google Scholar, R. J. Immunol. PubMed Scopus Google Scholar, M. J. Immunol. PubMed Scopus Google Scholar). show that calcium signaling through and CaMK-II, as as through PI3K positively regulated LPS-induced IL-12p40 production in human monocytic Moreover, both CyA and FK506 LPS-induced IL-12p40 production by inhibiting NFκB and AP-1 through the CaM/CaMK-II-activated PI3K and independent of the JNK pathway. of calcium signaling been shown to IL-12p40 production in murine monocytic of on murine monocytic cells LPS-induced IL-12p40 production that was by with the calcium C.M. Trinchieri G. Ma X. J. Immunol. 2001; PubMed Scopus Google Scholar, P. J. Med. 1998; PubMed Scopus Google Scholar, R. J. Med. 1997; PubMed Scopus Google Scholar). show that of LPS-induced calcium by IL-12p40 production in human monocytic A role calcium was by inhibitors is a key signaling protein to transcription factors J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). downstream of are calcineurin and J. PubMed Scopus (76) Google Scholar, A. K. S. T. Cell. 2003; PubMed Scopus Google Scholar). with other on a in a to and subunits thereby it a J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). by inhibitors CaM, and that LPS-induced IL-12p40 production is regulated by the pathway. that both FK506 and CyA LPS-induced in and IL-12p40 production in monocytic cells that be a by which these agents inhibit Th1 responses in these of to the calcium inhibitors with the cells be to the the PI3K of a subunit and and a catalytic and of the subunit with in or in the of to D. R. C. C. 1999; PubMed Scopus Google Scholar, U. J. A. J. 1998; PubMed Scopus Google Scholar, T. A. L.C. S. J. 2001; PubMed Scopus Google Scholar, J. L.C. 7: PubMed Scopus Google Scholar, S. PubMed Scopus Google Scholar) that to the of and of a of including protein kinase and protein kinase K. J. R. P.C. R. 2001; PubMed Scopus Google Scholar, J. L.C. 7: PubMed Scopus Google Scholar). is to that PI3K plays a key role in the of IL-12p40 production by murine DCs and monocytic cells T. S. Immunol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, T. M. T. S. T. T. T. S. Immunol. 2002; PubMed Scopus Google Scholar). PI3K was shown to negatively regulate IL-12p40 production by human monocytic cells by the LPS M. N. J. J. Immunol. 2003; PubMed Scopus Google Scholar) and of and in human and murine monocytic cells and DCs R. J. Immunol. PubMed Scopus Google Scholar, H. R. D. C. J. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar). we show that LPS-induced IL-12p40 production by human as as cells is regulated positively through PI3K the role and functions of PI3K been because of their to biological of PI3K inhibitors to inhibit of PI3K J. F. S. S.E. M.J. J. 1997; PubMed Scopus Google Scholar), and PI3K p110α or 2002; 13: PubMed Scopus Google Scholar, A. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). is to that the subunit independent of the p110α regulate the expression of including H. H. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J. L.C. PubMed Scopus Google Scholar). an the p110α subunit of PI3K was shown to regulate and of in monocytic cells A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, we have that cells in the expression of the p110α catalytic of PI3K produced of IL-12p40 in to LPS on the expression of and not that PI3K LPS-induced IL-12p40 production. of in with the of LPS-induced IL-12p40 production through the JNK pathway W. K. W. K. M. A. J. Immunol. PubMed Scopus Google Scholar) that LPS-induced IL-12p40 production is regulated by signaling pathways the PI3K pathway and the JNK pathway. Interestingly, both pathways regulated IL-12p40 production through the activation of NFκB and AP-1 transcription factors. It is not the JNK pathway to LPS-induced IL-12p40 production in the of inhibitors the calcium pathway. to signal transduction mechanisms expression and J.R. J. Cell. 2000; 35: PubMed Google Scholar, A. J. Cell. 7: PubMed Scopus Google Scholar, R. PubMed Scopus Google Scholar). the of and the mechanisms underlying the of signaling pathways IL-12p40 we have shown that IL-12p40 production is regulated by and AP-1 through the activation of calcium and PI3K NFκB and AP-1 are known to be activated by the K. S. A. T. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, N. M. T. J. Med. PubMed Scopus Google Scholar), it is not and with the of the NFκB and AP-1 It is also not that in the of an both of these transcription factors to IL-12p40 Although to the role of transcription factors not a the of the these transcription factors be It is that the of these transcription factors is with other signaling activated by are to the NFκB and AP-1 and other factors in IL-12p40 role of IL-12p40 in the of IL-12 and that it be in the of and autoimmune the underlying the inhibitory effects of CyA and FK506 on IL-12p40 production have the a role of calcium and PI3K and in particular a of p110α subunit of PI3K in IL-12 production by human the of agents of inhibiting calcium and PI3K pathways as to IL-12 production. that calcium and PI3K signaling pathways positively regulate human IL-12p40 production in to their role in murine IL-12p40 production the of in the in the production of critical cytokines IL-12 and in human

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.

La notice

Revue

Journal of Biological Chemistry

Thématique

Signaling Pathways in Disease

Domaine

Biochemistry, Genetics and Molecular Biology

Établissements canadiens

Vancouver Coastal Health Research InstituteVancouver Coastal HealthUniversity of British ColumbiaOttawa HospitalChildren's Hospital of Eastern OntarioUniversity of Ottawa

Organismes subventionnaires

—

Mots-clés

Phosphoinositide 3-kinaseCell biologyCalcineurinCalmodulinCAMKPI3K/AKT/mTOR pathwayKinaseProtein kinase ABiologySignal transductionChemistryBiochemistryInternal medicineEnzymeMedicine

Résumé présent dans OpenAlex

oui

API

/api/v1/works/W2084865513