MAPK signalling pathways as molecular targets for anti-inflammatory therapy--from molecular mechanisms to therapeutic benefits.
Excessive inflammation is becoming accepted as a critical factor in many human diseases, including inflammatory and autoimmune disorders, neurodegenerative conditions, infection, cardiovascular diseases, and cancer. Cerebral ischemia and neurodegenerative diseases are accompanied by a marked inflammatory reaction that is initiated by expression of cytokines, adhesion molecules, and other inflammatory mediators, including prostanoids and nitric oxide. This review discusses recent advances regarding the detrimental effects of inflammation, the regulation of inflammatory signalling pathways in various diseases, and the potential molecular targets for anti-inflammatory therapy. Mitogen-activated protein kinases (MAPKs) are a family of serine/threonine protein kinases that mediate fundamental biological processes and cellular responses to external stress signals. Increased activity of MAPK, in particular p38 MAPK, and their involvement in the regulation of the synthesis of inflammation mediators at the level of transcription and translation, make them potential targets for anti-inflammatory therapeutics. Inhibitors targeting p38 MAPK and JNK pathways have been developed, and preclinical data suggest that they exhibit anti-inflammatory activity. This review discusses how these novel drugs modulate the activity of the p38 MAPK and JNK signalling cascades, and exhibit anti-inflammatory effects in preclinical disease models, primarily through the inhibition of the expression of inflammatory mediators. Use of MAPK inhibitors emerges as an attractive strategy because they are capable of reducing both the synthesis of pro-inflammatory cytokines and their signalling. Moreover, many of these drugs are small molecules that can be administered orally, and initial results of clinical trials have shown clinical benefits in patients with chronic inflammatory disease.
Kaminska
Bozena
B
Department of Cell Biology, Laboratory of Transcription Regulation, Nencki Institute of Experimental Biology, 3 Pasteur Str., 02-093 Warsaw, Poland. bozenakk@nencki.gov.pl
D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology; D048670:MAP Kinase Kinase 4 / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4