Growth factor and cytokine regulation of chondroitin sulfate proteoglycans by astrocytes.
After injury to the adult central nervous system (CNS), numerous cytokines and growth factors are released that contribute to reactive gliosis and extracellular matrix production. In vitro examination of these cytokines revealed that the presence of transforming growth factor-beta1 (TGF-beta1) and epidermal growth factor (EGF) greatly increased the production of several chondroitin sulfate proteoglycans (CSPG) by astrocytes. Treatment of astrocytes with other EGF-receptor (ErbB1) ligands, such as TGF-alpha and HB-EGF, produced increases in CSPG production similar to those observed with EGF. Treatment of astrocytes, however, with heregulin, which signals through other members of the EGF-receptor family (ErbB2, ErbB3, ErbB4), did not induce CSPG upregulation. The specificity of activation through the ErbB1 receptor was further verified by using a selective antagonist (AG1478) to this tyrosine kinase receptor. Western blot analysis of astrocyte supernatant pre-digested with chondroitinase ABC indicated the presence of multiple core proteins containing 4-sulfated or 6-sulfated chondroitin. To identify some of these CSPGs, Western blots were screened using antibodies to several known CSPG core proteins. These analyses showed that treatment of astrocytes with EGF increased phosphacan expression, whereas treatment with TGF-beta1 increased neurocan expression. Reverse transcription-polymerase chain reaction (RT-PCR) was used to examine the expression of these molecules in vivo, which result in increased expression of TGF-beta1, EGF-receptor, neurocan, and phosphacan after injury to the brain. These data begin to elucidate some of the injury-induced growth factors that regulate the expression of CSPGs which could be targeted in the future to modulate CSPG production after injury to the central nervous system.
Smith
George M
GM
Department of Physiology, University of Kentucky, Albert B. Chandler Medical Center, Lexington, KY 40536-0298, USA. GMSmith@uky.edu
Strunz
Celia
C
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001930:Brain Injuries / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists / Q000378:metabolism; D005911:Gliosis / Q000378:metabolism* / Q000503:physiopathology; D006133:Growth Substances / Q000378:metabolism*; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058580:Neurocan; D051381:Rats; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D011508:Chondroitin Sulfate Proteoglycans; D016207:Cytokines; D006133:Growth Substances; D037181:Lectins, C-Type; D009419:Nerve Tissue Proteins; D058580:Neurocan; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C076817:NCAN protein, human; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C516895:PTPRZ1 protein, human; C516897:Ptprz1 protein, rat; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5