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Dexamethasone inhibits IL-12p40 production in lipopolysaccharide-stimulated human monocytic cells by down-regulating the activity of c-Jun N-terminal kinase, the activation protein-1, and NF-kappa B transcription factors.
J Immunol. 2004 Jan 01; 172(1):318-30.JI

Abstract

IL-12 plays a critical role in the development of cell-mediated immune responses and in the pathogenesis of inflammatory and autoimmune disorders. Dexamethasone (DXM), an anti-inflammatory glucocorticoid, has been shown to inhibit IL-12p40 production in LPS-stimulated monocytic cells. In this study, we investigated the molecular mechanism by which DXM inhibits IL-12p40 production by studying the role of the mitogen-activated protein kinases (MAPKs), and the key transcription factors involved in human IL-12p40 production in LPS-stimulated monocytic cells. A role for c-Jun N-terminal kinase (JNK) MAPK in LPS-induced IL-12p40 regulation in a promonocytic THP-1/CD14 cell line was demonstrated by using specific inhibitors of JNK activation, SP600125 and a dominant-negative stress-activated protein/extracellular signal-regulated kinase kinase-1 mutant. To identify transcription factors regulating IL-12p40 gene transcription, extensive deletion analyses of the IL-12p40 promoter was performed. The results revealed the involvement of a sequence encompassing the AP-1-binding site, in addition to that of NF-kappaB. The role of AP-1 in IL-12p40 transcription was confirmed by using antisense c-fos and c-jun oligonucleotides. Studies conducted to understand the regulation of AP-1 and NF-kappaB activation by JNK MAPK revealed that both DXM and SP600125 inhibited IL-12p40 gene transcription by inhibiting the activation of AP-1 and NF-kappaB transcription factors as revealed by luciferase reporter and gel mobility shift assays. Taken together, our results suggest that DXM may inhibit IL-12p40 production in LPS-stimulated human monocytic cells by down-regulating the activation of JNK MAPK, the AP-1, and NF-kappaB transcription factors.

Authors+Show Affiliations

Department of Pediatrics, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14688340

Citation

Ma, Wei, et al. "Dexamethasone Inhibits IL-12p40 Production in Lipopolysaccharide-stimulated Human Monocytic Cells By Down-regulating the Activity of c-Jun N-terminal Kinase, the Activation Protein-1, and NF-kappa B Transcription Factors." Journal of Immunology (Baltimore, Md. : 1950), vol. 172, no. 1, 2004, pp. 318-30.
Ma W, Gee K, Lim W, et al. Dexamethasone inhibits IL-12p40 production in lipopolysaccharide-stimulated human monocytic cells by down-regulating the activity of c-Jun N-terminal kinase, the activation protein-1, and NF-kappa B transcription factors. J Immunol. 2004;172(1):318-30.
Ma, W., Gee, K., Lim, W., Chambers, K., Angel, J. B., Kozlowski, M., & Kumar, A. (2004). Dexamethasone inhibits IL-12p40 production in lipopolysaccharide-stimulated human monocytic cells by down-regulating the activity of c-Jun N-terminal kinase, the activation protein-1, and NF-kappa B transcription factors. Journal of Immunology (Baltimore, Md. : 1950), 172(1), 318-30.
Ma W, et al. Dexamethasone Inhibits IL-12p40 Production in Lipopolysaccharide-stimulated Human Monocytic Cells By Down-regulating the Activity of c-Jun N-terminal Kinase, the Activation Protein-1, and NF-kappa B Transcription Factors. J Immunol. 2004 Jan 1;172(1):318-30. PubMed PMID: 14688340.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dexamethasone inhibits IL-12p40 production in lipopolysaccharide-stimulated human monocytic cells by down-regulating the activity of c-Jun N-terminal kinase, the activation protein-1, and NF-kappa B transcription factors. AU - Ma,Wei, AU - Gee,Katrina, AU - Lim,Wilfred, AU - Chambers,Kelly, AU - Angel,Jonathan B, AU - Kozlowski,Maya, AU - Kumar,Ashok, PY - 2003/12/23/pubmed PY - 2004/4/3/medline PY - 2003/12/23/entrez SP - 318 EP - 30 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 172 IS - 1 N2 - IL-12 plays a critical role in the development of cell-mediated immune responses and in the pathogenesis of inflammatory and autoimmune disorders. Dexamethasone (DXM), an anti-inflammatory glucocorticoid, has been shown to inhibit IL-12p40 production in LPS-stimulated monocytic cells. In this study, we investigated the molecular mechanism by which DXM inhibits IL-12p40 production by studying the role of the mitogen-activated protein kinases (MAPKs), and the key transcription factors involved in human IL-12p40 production in LPS-stimulated monocytic cells. A role for c-Jun N-terminal kinase (JNK) MAPK in LPS-induced IL-12p40 regulation in a promonocytic THP-1/CD14 cell line was demonstrated by using specific inhibitors of JNK activation, SP600125 and a dominant-negative stress-activated protein/extracellular signal-regulated kinase kinase-1 mutant. To identify transcription factors regulating IL-12p40 gene transcription, extensive deletion analyses of the IL-12p40 promoter was performed. The results revealed the involvement of a sequence encompassing the AP-1-binding site, in addition to that of NF-kappaB. The role of AP-1 in IL-12p40 transcription was confirmed by using antisense c-fos and c-jun oligonucleotides. Studies conducted to understand the regulation of AP-1 and NF-kappaB activation by JNK MAPK revealed that both DXM and SP600125 inhibited IL-12p40 gene transcription by inhibiting the activation of AP-1 and NF-kappaB transcription factors as revealed by luciferase reporter and gel mobility shift assays. Taken together, our results suggest that DXM may inhibit IL-12p40 production in LPS-stimulated human monocytic cells by down-regulating the activation of JNK MAPK, the AP-1, and NF-kappaB transcription factors. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/14688340/Dexamethasone_inhibits_IL_12p40_production_in_lipopolysaccharide_stimulated_human_monocytic_cells_by_down_regulating_the_activity_of_c_Jun_N_terminal_kinase_the_activation_protein_1_and_NF_kappa_B_transcription_factors_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=14688340 DB - PRIME DP - Unbound Medicine ER -