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[Transplantation immunology and immunosuppressive drug]
1National Children's Medical Research Center, Department of Experimental Surgery and Bioengineering, Tokyo, Japan.
Abstract:
Tyrosine kinases (TK) and G proteins act as second, messengers for intracellular signal transduction. TK activates the cascade of protein phosphorylation. G proteins are heterodimer complex with alpha, beta, and gamma subunits. PLC activated by GTP-binding alpha subunit lyses membrane phosphatidyl inositol (PI), releasing diacyl glycerol (DAG) and inositol trisphosphate (IP3). IP3 releases calcium into cytoplasm to activate calcineurin, causing a NF-AT cytoplasmic factor (NF-ATc) to translocate to nucleus. DAG activates protein kinase C (PKC), which synthesizes another nuclear factor NF-ATn. When NF-ATc and NF-ATn assemble to form the complex on the promoter site of DNA, transcription of IL-2 mRNA begins. PKC also induces phosphorylation of I-kappa B to release NF-kappa B. The complex of CsA or FK506 with CyP or FKBP, respectively, inhibits the activation of calcineurin. FKBP-binding rapamycin inhibits cell proliferation and differentiation by inactivation of p70 s6 kinase. RS61443 and mizoribine influence specifically on the de novo pathway of purine biosynthesis. DSG may bind to Hsc 70 and inhibit the translocation of NF-kappa B into nucleus. FTY720 induces lymphocyte-specific apoptosis, independently on Fas-antigen expressions. by modulating bcl-2 genes.
Insights
This study explains how tyrosine kinases and G proteins mediate intracellular signals, leading to IL-2 mRNA transcription. It also details how various drugs inhibit these pathways, impacting immune responses.
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Immunology
Context:
- Tyrosine kinases (TK) and G proteins are crucial for intracellular signal transduction.
- TKs initiate protein phosphorylation cascades, while G proteins regulate enzymes like phospholipase C (PLC).
- PLC activation by G proteins releases diacylglycerol (DAG) and inositol trisphosphate (IP3), key second messengers.
Purpose:
- To elucidate the molecular mechanisms of intracellular signal transduction involving TKs and G proteins.
- To describe the pathways leading to Interleukin-2 (IL-2) mRNA transcription.
- To outline the inhibitory actions of various immunosuppressive drugs on these signaling cascades.
Summary:
- G protein alpha subunits activate PLC, generating DAG and IP3. IP3 triggers calcium release, activating calcineurin and NF-ATc translocation. DAG activates protein kinase C (PKC), leading to NF-ATn synthesis.
- Nuclear factors NF-ATc and NF-ATn form a complex, initiating IL-2 mRNA transcription. PKC also releases NF-kappa B by phosphorylating I-kappa B.
- Immunosuppressants like CsA/FK506 inhibit calcineurin. Rapamycin blocks cell proliferation by inhibiting p70 s6 kinase. RS61443/mizoribine target purine biosynthesis. DSG inhibits NF-kappa B nuclear translocation. FTY720 induces lymphocyte apoptosis via bcl-2 modulation.
Impact:
- Understanding these pathways is vital for developing targeted therapies for immune-related diseases.
- The study highlights multiple drug targets within the IL-2 signaling cascade and immune cell regulation.
- This research provides a foundation for exploring novel immunosuppressive strategies and understanding drug mechanisms of action.