| Summary: | 博士 === 國立臺灣大學 === 藥理學研究所 === 104 === Cytokines are small molecular polypeptides that mainly secreted by immune cells. They play a pivotal role in signaling transduction and are involved in a wide range of biological activities. In addition to their role in immune system, cytokines are also linked with numerous diseases. In this thesis, we tried to (1) examine the role of cytokines in the pathogenesis of rheumatoid arthritis (RA), and (2) to elucidate the effect of cytokines in pain management.
Rheumatoid arthritis (RA) is an autoimmune disease. The cause of RA is still obscure, although a genetic component and environmental factors appear likely. In RA patients, numerous of immune cells accumulate in the joint, leading to activate osteoclast and stimulate synovial fibroblast (SF) to secret lots of cytokines such as IL-1β, IL-6 and TNF-α eventually lead to cartilage erosion and joint destruction. Previous studies have shown that the levels of oncostatin M (OSM) are upregulated in RA patients’ synovial fluid, but how OSM participates in RA is still unclear. Here we found that OSM could increase the mRNA and protein levels of placenta growth actor (PLGF) in RA synovial fibroblast (RASF) derived from RA patients. The enhancement effect of OSM was antagonized by the addition of Jak and PI3K inhibitors. Treatment of OSM in RASF could activate Jak/STAT and PI3K/Akt signaling pathways, activated-STAT will further translocate into nucleus and bind to the promoter region of PLGF. The accumulation of PLGF may contribute to inflammation and angiogenesis of RA. These results revealed that OSM could be a good target for developing drugs to treat RA.
To the patients who have moderate to severe RA, persistent pain is the most annoying problem. Clinicians sometimes use opioids to reduce severe pain when traditional painkiller not able to control pain. However, long-term use of opioids is usually confined by the development of tolerance, which means a higher dose is required to achieve the same analgesic level. Higher doses of opioids are associated with more serious side effects including constipation, nausea, dizziness and respiratory depression. In our second and third studies, we found that long-term treatment of morphine could increase the levels of OSM and leukemia inhibitory factor (LIF) in rat spinal cord. The upregulated OSM and LIF could potentiate the analgesic effect of morphine by enhancing the effect of opioid on potassium outward current in dorsal horn neurons. Moreover, OSM and LIF could markedly attenuate the development of tolerance by suppressing microglia activation. We further collected sample from patients with different degrees of opioid tolerant cancer patients and compared with opioid naive surgical patients. It was found that the levels of LIF were significantly higher in opioid tolerant patients, there was a positive correlation between daily equivalent opioid dose and LIF expression. These results indicate that LIF might be a novel target to inhibit the development of opioid tolerance.
In summary, our results implicate novel mechanism of OSM and LIF in the pathogenesis of RA and in the development of opioid tolerance. These chemokines may be a good drug target for developing new drugs.
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