Inhibition of a novel specific neuroglial integrin signaling pathway increases STAT3-mediated CNTF expression
- PDF / 1,013,069 Bytes
- 15 Pages / 595.28 x 793.7 pts Page_size
- 15 Downloads / 253 Views
RESEARCH
Open Access
Inhibition of a novel specific neuroglial integrin signaling pathway increases STAT3-mediated CNTF expression Matthew P Keasey1, Seong Su Kang1, Chiharu Lovins1 and Theo Hagg1,2*
Abstract Background: Ciliary neurotrophic factor (CNTF) expression is repressed in astrocytes by neuronal contact in the CNS and is rapidly induced by injury. Here, we defined an inhibitory integrin signaling pathway. Results: The integrin substrates laminin, fibronectin and vitronectin, but not collagen, thrombospondin or fibrinogen, reduced CNTF expression in C6 astroglioma cells. Antibodies against αv and β5, but not α6 or β1, integrin induced CNTF. Together, the ligand and antibody specificity suggests that CNTF is repressed by αvβ5 integrin. Antibodies against Thy1, an abundant neuronal surface protein whose function is unclear, induced CNTF in neuron-astrocyte co-cultures indicating that it is a neuroglial CNTF repressor. Inhibition of the integrin signaling molecule Focal Adhesion Kinase (FAK) or the downstream c-Jun N-terminal kinase (JNK), but not extracellular regulated kinase (ERK) or p38 MAPK, greatly induced CNTF mRNA and protein expression within 4 hours. This selective inhibitory pathway phosphorylated STAT3 on its inhibitory ser-727 residue interfering with activity of the pro-transcription Tyr-705 residue. STAT3 can activate CNTF transcription because it bound to its promoter and FAK antagonist-induced CNTF was reduced by blocking STAT3. Microinjection of FAK inhibitor directly into the brain or spinal cord in adult mice rapidly induced CNTF mRNA and protein expression. Importantly, systemic treatment with FAK inhibitors over 3 days induced CNTF in the subventricular zone and increased neurogenesis. Conclusions: Neuron-astroglia contact mediated by integrins serves as a sensor to enable rapid neurotrophic responses and provides a new pharmacological avenue to exploit the neuroprotective properties of endogenous CNTF. Keywords: Astrocyte, Ciliary neurotrophic factor, Focal adhesion kinase, Integrin, Intercellular communication, Mice, Neurogenesis, Neuron, Pharmacological, Transcriptional gene regulation
Background Endogenous CNTF regulates the development of oligodendrocytes [1] and some neurons [2], synaptic function [3], and adult CNS neurogenesis [4,5]. CNTF treatment is neuroprotective in many animal models [6-10], and promotes retinal ganglion cell regeneration [11,12] and remyelination [13]. Even so, clinical trials failed due to low penetration of CNTF into the CNS and systemic side effects after subcutaneous injections [14]. CNTF is almost exclusively expressed in the nervous system, suggesting * Correspondence: [email protected] 1 Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville, Louisville, KY 40292, USA 2 Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292, USA
that its pharmacological induction might solve these problems. In the CNS, CNTF is produced at very low levels primarily by astrocytes [15] bu
Data Loading...
