ReviewInhibition of p38 MAP kinase as a therapeutic strategy
Section snippets
p38 MAP kinase homologs
As is the case with both ERKs and JNKs, multiple members of the p38 MAP kinase family have been identified (Cobb and Goldsmith, 1995). Murine p38 was first identified as a kinase activated in response to bacterial LPS (Han et al., 1994). Soon after, human CSBP1 and CSBP2/p38 were identified as targets of a class of pyridinylimidazole compounds that inhibited the production of inflammatory cytokines from activated monocyte/macrophages (Lee et al., 1994). CSBP1 and CSBP2 differ from each other by
Substrates
A number of substrates of p38 MAP kinase have been identified. These include other kinases such as MAPKAP K2/3, p38-regulated/activated protein kinase (PRAK), MAP kinase-interacting kinase 1 and 2 (MNK1/2), mitogen and stress-activated kinase 1 (MSK1)/RLPK, and ribosomal S6 kinase-B (RSK-B); transcription factors such as activation transcription factors 2 and 6 (ATF2/6), myocyte enhancer factor 2C (MEF2C), C/EBP homologous protein (CHOP), Elk1 and SAP-1A and cytosolic proteins such as stathmin.
Signaling pathways involving p38 MAP kinase
Significant progress has been made in defining the exact molecular pathways of p38 MAP kinase activation and subsequent signaling. Members of the p38 MAP kinase family are phosphorylated on Thr and Tyr residues in a Thr-Gly-Tyr motif by a dual specificity MKK. Initially, it was thought that among upstream MKKs, MKK 3, 4 and 6 all activated p38 MAP kinase Derijard et al., 1995, Han et al., 1996, Raingeaud et al., 1996. However, recent data suggest that MKK6 and, under certain conditions, MKK3
Role of p38 MAP kinase in cytokine production and function
The role of p38 MAP kinase in the regulation of cytokine production or function was not appreciated until the discovery of p38 MAP kinase activation in LPS stimulated macrophages (Han et al., 1994) and the simultaneous identification of the molecular target of compounds previously shown to inhibit cytokine biosynthesis (Lee et al., 1994). It is now known that the regulation of cytokine biosynthesis in many different cell types is regulated through activation of p38 MAP kinase Beyaert et al.,
p38 MAP kinase and hematopoietic cells
In murine T-cells, the p38 MAP kinase inhibitor, SB 203580 inhibited the production of interferon-gamma by Th1 cells without affecting IL-4 production by Th2 cells (Rincon et al., 1998). Overexpression of dominant-negative p38 MAP kinase results in selective impairment of Th1 responses whereas constitutively activated MKK6 overexpression caused increased production of interferon-gamma. In another study, it was shown that SB 203580 inhibited CD28-dependent T-cell proliferation and IL-2 in vitro
Inflammatory diseases
The widely used p38 MAP kinase inhibitor, SB 203580, has been profiled in a number of models in vivo and demonstrated its activity in a wide variety of TNF alpha mediated disease models (Badger et al., 1996). The compound inhibited LPS-induced TNF production with IC50 of 15 and 25 mg/kg in mice and rats, respectively. It was effective in reducing paw inflammation in the adjuvant arthritic rat with optimum inhibition observed at 60 mg/kg. There is also evidence for protection of joint integrity
Compounds
The bicylic pyridinylimidazole SKF 86002 was first reported to inhibit LPS-stimulated cytokine production Lee et al., 1988, Lee et al., 1993, Lee et al., 1994, Lee et al., 1999. In 1993, the SAR for inhibition of cytokine synthesis by bicyclic imidazoles was described in a publication which explored dual 5-LO/COX and cytokine inhibition as potential mechanisms for the potent anti-inflammatory activity of these compounds (Lee et al., 1993). Subsequently, SB 203580, and other 2,4,5-triaryl
Conclusion and perspectives
Our increased understanding of the signal transduction pathways involved in the regulation of cytokine production and cytokine signaling in immune cells has opened the door for the discovery of novel therapeutics useful in treating a variety of inflammatory diseases in which cytokine production or signaling is implicated. The availability of potent and selective inhibitors of such signaling pathways also provide a means to further dissect the pathways to increase our understanding of the
References (137)
- et al.
Pyrimidinylimidazole inhibitors of CSBP/p38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes
Bioorg. Med. Chem. Lett.
(1998) - et al.
Cdc42 and PAK-mediated signaling leads to Jun kinase and p38 mitogen-activated protein kinase activation
J. Biol. Chem.
(1995) - et al.
Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2
Curr. Biol.
(1998) - et al.
Phosphorylation of the respiratory burst oxidase subunit p67(phox) during human neutrophil activation. Regulation by protein kinase C-dependent and independent pathways
J. Biol. Chem.
(1997) - et al.
How MAP kinases are regulated
J. Biol. Chem.
(1995) The search for physiological substrates of MAP and SAP kinases in mammalian cells
Trends Cell Biol.
(1997)- et al.
SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1
FEBS Lett.
(1995) - et al.
Pyrroles and other heterocycles as inhibitors of p38 kinase
Bioorg. Med. Chem. Lett.
(1998) - et al.
JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain
Cell
(1994) - et al.
Activation of the MAP kinase homologue RK requires the phosphorylation of Thr-180 and Tyr-182 and both residues are phosphorylated in chemically stressed KB cells
FEBS Lett.
(1995)
Selective activation of p38 mitogen-activated protein (MAP) kinase: isoforms by the kinase kinases MKK3 and MKK6
J. Biol. Chem.
Conversion of SB 203580-insensitive MAP kinase family members to drug-sensitive forms by a single amino-acid substitution
Chem. Biol.
Human mitogen-activated protein kinase kinase 7 (MKK7) is a highly conserved c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activated by environmental stresses and physiological stimuli
J. Biol. Chem.
2,4,5-Triarylimidazole inhibitors of IL-1 biosynthesis
Bioorg. Med. Chem. Lett.
Regulation of stress-induced cytokine production by pyridinylimidazoles: inhibition of CSBP kinase
Bioorg. Med. Chem.
Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases
FEBS Lett.
Acquisition of sensitivity of stress-activated protein kinases to the p38 inhibitor, SB 203580, by alteration of one or more amino acids within the ATP binding pocket
J. Biol. Chem.
Characterization of the structure and function of a novel MAP kinase kinase (MKK6)
J. Biol. Chem.
The role of p38 MAP kinase in TGF-beta-induced signal transduction in human neutrophils
Biochem. Biophys. Res. Commun.
Stress-activated protein kinase-3 interacts with the PDZ domain of alpha1-syntrophin. A mechanism for specific substrate recognition
J. Biol. Chem.
LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils
J. Biol. Chem.
Apoptosis signaling pathway in T cells is composed of ICE/Ced-3 family proteases and MAP kinase kinase 6b
Immunity
MAP kinase-dependent transcriptional coactivation by Elk-1 and its cofactor CBP
Biochem. Biophys. Res. Commun.
Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta)
J. Biol. Chem.
Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38delta
J. Biol. Chem.
Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies
Immunity
Thrombin induces activation of p38 MAP kinase in human platelets
J. Biol. Chem.
Hyperosmolality causes growth arrest of murine kidney cells. Induction of GADD45 and GADD153 by osmosensing via stress-activated protein kinase 2
J. Biol. Chem.
Novel homologues of CSBP/p38 MAP kinase: activation, substrate specificity and sensitivity to inhibition by pyridinyl imidazoles
Biochem. Biophys. Res. Commun.
Pyridinylimidazole compound SB 203580 inhibits the activity but not the activation of p38 mitogen-activated protein kinase
Biochem. Biophys. Res. Commun.
Inhibition of monocyte IL-1 production by the anti-inflammatory compound SK&F 86002
Int. J. Immunopharmacol.
p38 mitogen-activated protein kinase inhibitors ā mechanisms and therapeutic potentials
Pharmacol. Ther.
The primary structure of p38 gamma: a new member of p38 group of MAP kinases
Biochem. Biophys. Res. Commun.
Rapid and long-lasting suppression of the ATF-2 transcription factor is a common response to neuronal injury
Brain Res. Mol. Brain Res.
T lymphocyte activation signals for interleukin-2 production involve activation of MKK6-p38 and MKK7-SAPK/JNK signaling pathways sensitive to cyclosporin A
J. Biol. Chem.
Proinflammatory cytokine-induced and chemical mediator-induced IL-8 expression in human bronchial epithelial cells through p38 mitogen-activated protein kinase-dependent pathway
J. Allergy Clin. Immunol.
Localization of the human stress responsive MAP kinase-like CSAIDs binding protein (CSBP) gene to chromosome 6q21.3/21.2
Genomics
Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase
J. Biol. Chem.
SAP kinase-3, a new member of the family of mammalian stress-activated protein kinases
FEBS Lett.
Signalling through either the p38 or ERK mitogen-activated protein (MAP) kinase pathway is obligatory for phorbol ester and T cell receptor complex (TCR-CD3)-stimulated for phorbol ester and T cell receptor complex (TCR-CD3)-stimulated phosphorylation of initiation factor (eIF) 4E in Jurkat T cells
FEBS Lett.
Involvement of stress-activated protein kinase and p38/RK mitogen-activated protein kinase signaling pathways in the enhanced phosphorylation of initiation factor 4E in NIH 3T3 cells
J. Biol. Chem.
Activation of p38 mitogen-activated protein kinase by PYK2/related adhesion focal tyrosine kinase-dependent mechanism
J. Biol. Chem.
Identification of stathmin as a novel substrate for p38Ī“
Biochem. Biophys. Res. Commun.
RSK-B, a novel ribosomal S6 kinase family member, is a CREB kinase under dominant control of p38alpha mitogen-activated protein kinase (p38alphaMAPK)
J. Biol. Chem.
Kinetic model of the epidermal growth factor (EGF) receptor tyrosine kinase and a possible mechanism of its activation by EGF
J. Biol. Chem.
Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine
J. Biol. Chem.
A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins
Cell
Pharmacological profile of SB 203580, a selective inhibitor of CSBP/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function
J. Pharmacol. Exp. Ther.
SB 203580 inhibits p38 mitogen-activated protein kinase, nitric oxide production, and inducible nitric oxide synthase in bovine cartilage-derived chondrocytes
J. Immunol.
Inflammatory mediators of asthma: an update
Pharmacol. Rev.
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