Stem cell factor and its receptor c-Kit as targets for inflammatory diseases.
Stem cell factor (SCF), the ligand of the c-Kit receptor, is expressed by various structural and inflammatory cells in the airways. Binding of SCF to c-Kit leads to activation of multiple pathways, including phosphatidyl-inositol-3 (PI3)-kinase, phospholipase C (PLC)-gamma, Src kinase, Janus kinase (JAK)/Signal Transducers and Activators of Transcription (STAT) and mitogen activated protein (MAP) kinase pathways. SCF is an important growth factor for mast cells, promoting their generation from CD34+ progenitor cells. In vitro, SCF induces mast cells survival, adhesion to extracellular matrix and degranulation, leading to expression and release of histamine, pro-inflammatory cytokines and chemokines. SCF also induces eosinophil adhesion and activation. SCF is upregulated in inflammatory conditions both in vitro and in vivo, in human and mice. Inhibition of the SCF/c-Kit pathway leads to significant decrease of histamine levels, mast cells and eosinophil infiltration, interleukin (IL)-4 production and airway hyperresponsiveness in vivo. Taken together, these data suggest that SCF/c-Kit may be a potential therapeutic target for the control of mast cell and eosinophil number and activation in inflammatory diseases.
Reber
Laurent
L
EA 3771 Inflammation and Environment in Asthma, Université Louis Pasteur-Strasbourg-I, Faculté de Pharmacie, Illkirch, France. lreber@pharma.u-strasbg.fr
Da Silva
Carla A
CA
Frossard
Nelly
N
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism; D001549:Benzamides; D003872:Dermatitis / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism; D008958:Models, Molecular; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit