Differential effects of the bicyclic imidazoles on cytokine biosynthesis in human monocytes and endothelial cells

Lee, J. C.; Laydon, Jeffrey T.; White, John R.

doi:10.1007/bf01987633

Cited by 6 publications

(3 citation statements)

References 5 publications

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“…Studies of p38 MAPK signaling have been aided by the availability of pyridinyl imidazole compounds that are highly specific inhibitors of p38 MAPK (22). These inhibitors have been shown previously to block production of proinflammatory cytokines in vitro and in vivo (4,12,13,23,24). Young et al (13) reported that pyridinyl imidazole inhibitors reduced endotoxin-induced cytokine production in isolated human PBMC.…”

Section: Discussionmentioning

confidence: 99%

Role of p38 mitogen-activated protein kinase in HIV type 1 production in vitro

Shapiro

Heidenreich

Meintzer

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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The proinf lammatory cytokines interleukin (IL)-1 and tumor necrosis factor (TNF) promote HIV type 1 viral replication in vitro. In the present studies, HIV production was increased in the macrophagic U1 cell line expressing the HIV genome after exposure to IL-1␤, osmotic stress, or surface adhesion, suggesting a conf luence of signaling pathways for proinf lammatory cytokines and cell stressors. The p38 mitogen-activated protein kinase (MAPK) mediates both cytokine and stress responses; thus the role of this kinase in HIV production was investigated. HIV production as measured by p24 antigen correlated with changes in the expression of a specific (non-alpha) isoform of p38 MAPK. In the presence of a specific p38 MAPK inhibitor (p38 inh), IL-1␤-induced HIV production was suppressed by more than 90% and IL-1␤-induced IL-8 production was suppressed completely, both with IC 50 of 0.01 M. p38 inhibition blocked cell-associated p24 antigen and secreted virus to a similar extent. The p38 inh also decreased constitutive HIV production in freshly infected peripheral blood mononuclear cells by up to 50% (P < 0.05). Interruption of p38 MAPK activity represents a viable target for inhibition of HIV.

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Section: Discussionmentioning

confidence: 99%

Role of p38 mitogen-activated protein kinase in HIV type 1 production in vitro

Shapiro

Heidenreich

Meintzer

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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“…The pyridinyl imidazoles, typified by SB203580, have proven useful in investigating the role of p38 kinase in regulating transcription, translation, and cytoskeletal elements in response to various stress and cytokine stimuli, as well as its potential role in animal models of inflammatory disease (21)(22)(23)(24)(25)(26). However, there has not been to date a detailed understanding of how SB203580 binds and subsequently inhibits p38 kinase catalytic activity.…”

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confidence: 99%

Pyridinyl Imidazole Inhibitors of p38 Mitogen-activated Protein Kinase Bind in the ATP Site

Young¹,

McLaughlin

Kumar

et al. 1997

Journal of Biological Chemistry

542

363

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The site of action of a series of pyridinyl imidazole compounds that are selective inhibitors of p38 mitogenactivated protein kinase in vitro and block proinflammatory cytokine production in vivo has been determined. Using Edman sequencing, 125 I-SB206718 was shown to cross-link to the nonphosphorylated Escherichia coli-expressed p38 kinase at Thr 175 , which is proximal to the ATP binding site. Titration calorimetric studies with E. coli-expressed p38 kinase showed that SB203580 bound with a stoichiometry of 1:1 and that binding was blocked by preincubation of p38 kinase with the ATP analogue, FSBA (5-[p-(fluorosulfonyl)benzoyl]adenosine), which covalently modifies the ATP binding site. The intrinsic ATPase activity of the nonphosphorylated enzyme was inhibited by SB203580 with a K m of 9.6 mM. Kinetic studies of active, phosphorylated yeast-expressed p38 kinase using a peptide substrate showed that SB203580 was competitive with ATP with a K i of 21 nM and that kinase inhibition correlated with binding and biological activity. Mutagenesis indicated that binding of 125 I-SB206718 was dependent on the catalytic residues K53 and D168 in the ATP pocket. These findings indicate that the pyridinyl imidazoles act in vivo by inhibiting p38 kinase activity through competition with ATP and that their selectivity is probably determined by differences in nonconserved regions within or near the ATP binding pocket.

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“…In IL-1-stimulated U1 cells and human peripheral blood mononuclear cells freshly infected with HIV-1, a specific inhibitor of p38 MAPK suppresses HIV-1 production (38). The pyridinyl imidazole compound SB 203580 specifically binds to and inactivates p38 MAPK (39,40); therefore, U1 cells were preincubated with the p38 MAPK inhibitor (0.00032-5.0 M) for 1 h and then stimulated with IL-18. Cultures were conducted in polypropylene tubes for 24 h. As shown in Fig.…”

Section: Mature But Not Pro-il-18mentioning

confidence: 99%