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High output of prostaglandins (PGs) are the hallmark of inflammatory and immune reactions. A rate-limiting step in the production of PGs is the presence of the enzyme cyclooxygenase (COX). COX exists as two isoforms: COX-1 which is constitutively expressed in most cells and COX-2 which is inducible by LPS, proinflammatory cytokines and other stimuli in cells involved in inflammation. The objective of this study was to determine the effect of nonsteroidal antiinflammatory drugs and proinflammatory cytokines on COX-2 expression in human macrophages. COX-2 specific (NS-398) and non-specific (aspirin, indomethacin and naproxen) inhibitors showed no effect on COX mRNA and protein expression induced by LPS. In contrast, the drugs markedly inhibited COX activity as measured by the accumulation of PGE2. The induction of COX-2 mRNA expression by LPS was rapid and sustained. However, LPS only transiently stimulated the transcription of COX-2 gene and activation of the transcription factor NF-kappaB. LPS stimulated the release of IL-1beta and TNF-alpha but these cytokines had no autocrine effect on the transcriptional or post-transcriptional regulation of COX-2. The presence of LPS was essential for the maintenance of high levels of long-lived COX-2 mRNA. As IFN-gamma is a major macrophage activating factor, we determined the role of this cytokine on COX-2 expression induced by exogenous IL-1beta. IFN-gamma-primed macrophages showed significantly lower levels of COX-2 mRNA, protein and PGE2 production compared to non-primed cells. IFN-gamma specifically decreased the transcriptional activation of COX-2 gene by IL-1beta but not by LPS without affecting the rate of mRNA decay. These results demonstrate that sustained production of PGE2 by macrophages in an inflammatory milieu can occur through the stabilization of COX-2 mRNA and revealed a role for IFN-gamma as an anti-inflammatory cytokine counteracting the expression of COX-2. A better understanding of COX-2 regulation will

Includes list of publications arising from this thesis / Erratum attached to inside back cover. / "25/03/2004." / Includes bibliographical references (leaves 185-257) / xii, 257 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine and Royal Adelaide Hospital, Rheumatology Unit, 2004

Bibliography: leaves 211-260 / xvii, 260 leaves ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Pathology, 1986

Ko, Wai Man. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 243-257). / Abstracts in English and Chinese. / Publications Based On The Work In This Thesis --- p.i / Abstract --- p.ii / Acknowledgements --- p.ix / Abbreviations --- p.x / Chapter Chapter 1 --- Introduction / Chapter 1.1 --- Prevalence of arthritis --- p.1 / Chapter 1.2 --- Pathogenesis of arthritis --- p.4 / Chapter 1.2.1 --- Histological changes --- p.6 / Chapter 1.2.1.1 --- Synovium changes --- p.6 / Chapter 1.2.1.2 --- Articular cartilage degradation --- p.8 / Chapter 1.2.1.3 --- Bone erosions --- p.10 / Chapter 1.3 --- Western medicines for arthritis --- p.14 / Chapter 1.3.1 --- Nonsteroidal anti-inflammatory drugs (NSAIDs) --- p.15 / Chapter 1.3.2 --- Glucocorticoids (GCs) --- p.18 / Chapter 1.3.3 --- Disease modifying antirheumatic drugs (DMARDs) --- p.20 / Chapter 1.3.4 --- Biological therapies --- p.22 / Chapter 1.4 --- Traditional Chinese medicines for arthritis --- p.24 / Chapter 1.4.1 --- Ganoderma lucidum (靈芝））) --- p.26 / Chapter 1.4.1.1 --- Major chemical constituents --- p.27 / Chapter 1.4.1.2 --- Functions --- p.27 / Chapter 1.4.2 --- Cortex Phellodendri (黃柏） --- p.28 / Chapter 1.4.2.1 --- Major chemical constituents --- p.29 / Chapter 1.4.2.2 --- Traditional description --- p.29 / Chapter 1.4.2.3 --- Functions --- p.30 / Chapter 1.4.3 --- Atractylodisa Rhizoma (蒼术) --- p.31 / Chapter 1.4.3.1 --- Major chemical constituents --- p.31 / Chapter 1.4.3.2 --- Traditional description --- p.32 / Chapter 1.4.3.3 --- Functions --- p.32 / Chapter 1.4.4 --- Radix Achyranthis Bidentatae (牛膝) --- p.33 / Chapter 1.4.4.1 --- Major chemical constituents --- p.34 / Chapter 1.4.4.2 --- Traditional description --- p.34 / Chapter 1.4.4.3 --- Functions --- p.34 / Chapter 1.5 --- Animal models of arthritis --- p.36 / Chapter 1.5.1 --- Adjuvant-induced arthritis --- p.37 / Chapter 1.6 --- Aims of study --- p.42 / Chapter Chapter 2 --- Materials and Drugs --- p.44 / Chapter Chapter 3 --- Methodology --- p.49 / Chapter 3.1 --- Induction of anaesthesia --- p.49 / Chapter 3.2 --- Induction of monoarthritis --- p.49 / Chapter 3.3 --- Measurements of knee extension angles --- p.50 / Chapter 3.4 --- Measurements of knee joint sizes --- p.51 / Chapter 3.5 --- Assessment of changes in articular blood flow --- p.52 / Chapter 3.6 --- Assessment of morphological changes --- p.53 / Chapter 3.6.1 --- Fixation --- p.53 / Chapter 3.6.2 --- Decalcification --- p.53 / Chapter 3.6.3 --- Processing --- p.54 / Chapter 3.6.4 --- Embedding --- p.54 / Chapter 3.6.5 --- Sectioning --- p.55 / Chapter 3.6.6 --- Staining --- p.55 / Chapter 3.6.7 --- Scoring --- p.56 / Chapter 3.7 --- Statistical analysis --- p.57 / Chapter Chapter 4 --- Adjuvant-induced Monoarthritic Rats / Chapter 4.1 --- Adjuvant-induced monoarthritic rats (1 week) --- p.58 / Chapter 4.1.1 --- Method --- p.58 / Chapter 4.1.2 --- Results --- p.59 / Chapter 4.1.2.1 --- Body weight --- p.59 / Chapter 4.1.2.2 --- Knee joint sizes --- p.59 / Chapter 4.1.2.3 --- Knee extension angles --- p.59 / Chapter 4.1.2.4 --- Knee joint blood flow --- p.60 / Chapter 4.1.2.5 --- Histological evaluation --- p.60 / Chapter 4.1.2.5.1 --- Cell infiltration --- p.60 / Chapter 4.1.2.5.2 --- Synovial tissue proliferation --- p.61 / Chapter 4.1.2.5.3 --- Cartilage degradation --- p.61 / Chapter 4.2 --- Adjuvant-induced monoarthritic rats (2 weeks) --- p.68 / Chapter 4.2.1 --- Method --- p.68 / Chapter 4.2.2 --- Results --- p.69 / Chapter 4.2.2.1 --- Body weight --- p.69 / Chapter 4.2.2.2 --- Knee joint sizes --- p.69 / Chapter 4.2.2.3 --- Knee extension angles --- p.69 / Chapter 4.2.2.4 --- Knee joint blood flow --- p.70 / Chapter 4.2.2.5 --- Histological evaluation --- p.70 / Chapter 4.2.2.5.1 --- Cell infiltration --- p.70 / Chapter 4.2.2.5.2 --- Synovial tissue proliferation --- p.71 / Chapter 4.2.2.5.3 --- Cartilage degradation --- p.71 / Chapter 4.3 --- Discussions --- p.78 / Chapter Chapter 5 --- Effects of intra-articular injection of LS in adjuvant-induced monoarthritic rats --- p.82 / Chapter 5.1 --- Method --- p.82 / Chapter 5.2 --- Results --- p.83 / Chapter 5.2.1 --- Body weight --- p.83 / Chapter 5.2.2 --- Knee joint sizes --- p.83 / Chapter 5.2.3 --- Knee extension angles --- p.85 / Chapter 5.2.4 --- Knee joint blood flow --- p.87 / Chapter 5.3 --- Discussions --- p.98 / Chapter Chapter 6 --- Effects of oral administration of LS in adjuvant-induced monoarthritic rats --- p.102 / Chapter 6.1 --- Oral administration of LS for 6 days after induction of arthritis --- p.102 / Chapter 6.1.1 --- Method --- p.102 / Chapter 6.1.2 --- Results --- p.103 / Chapter 6.1.2.1 --- Body weight --- p.103 / Chapter 6.1.2.2 --- Knee joint sizes --- p.103 / Chapter 6.1.2.3 --- Knee extension angles --- p.105 / Chapter 6.1.2.4 --- Knee joint blood flow --- p.106 / Chapter 6.1.2.5 --- Histological evaluation --- p.107 / Chapter 6.1.2.5.1 --- Cell infiltration --- p.107 / Chapter 6.1.2.5.2 --- Synovial tissue proliferation --- p.107 / Chapter 6.1.2.5.3 --- Cartilage degradation --- p.108 / Chapter 6.2 --- Oral administration of LS for 7 days before and 7 days after induction of arthritis --- p.131 / Chapter 6.2.1 --- Method --- p.131 / Chapter 6.2.2 --- Results --- p.132 / Chapter 6.2.2.1 --- Body weight --- p.132 / Chapter 6.2.2.2 --- Knee joint sizes --- p.132 / Chapter 6.2.2.3 --- Knee extension angles --- p.134 / Chapter 6.2.2.4 --- Knee joint blood flow --- p.137 / Chapter 6.2.2.5 --- Histological evaluation --- p.137 / Chapter 6.2.2.5.1 --- Cell infiltration --- p.137 / Chapter 6.2.2.5.2 --- Synovial tissue proliferation --- p.138 / Chapter 6.2.2.5.3 --- Cartilage degradation --- p.138 / Chapter 6.3 --- Oral administration of LS for 13 days after induction of arthritis --- p.165 / Chapter 6.3.1 --- Method --- p.165 / Chapter 6.3.2 --- Results --- p.166 / Chapter 6.3.2.1 --- Body weight --- p.166 / Chapter 6.3.2.2 --- Knee joint sizes --- p.166 / Chapter 6.3.2.3 --- Knee extension angles --- p.168 / Chapter 6.3.2.4 --- Knee joint blood flow --- p.169 / Chapter 6.3.2.5 --- Histological evaluation --- p.170 / Chapter 6.3.2.5.1 --- Cell infiltration --- p.170 / Chapter 6.3.2.5.2 --- Synovial tissue proliferation --- p.170 / Chapter 6.3.2.5.3 --- Cartilage degradation --- p.171 / Chapter 6.4 --- Discussions --- p.194 / Chapter Chapter 7 --- Effects of intra-peritoneal administration of LS in adjuvant-induced monoarthritic rats --- p.203 / Chapter 7.1 --- Method --- p.203 / Chapter 7.2 --- Results --- p.204 / Chapter 7.2.1 --- Body weight --- p.204 / Chapter 7.2.2 --- Knee joint sizes --- p.205 / Chapter 7.2.3 --- Knee extension angles --- p.207 / Chapter 7.2.4 --- Knee joint blood flow --- p.209 / Chapter 7.2.5 --- Histological evaulation --- p.209 / Chapter 7.2.5.1 --- Cell infiltration --- p.209 / Chapter 7.2.5.2 --- Synovial tissue proliferation --- p.210 / Chapter 7.2.5.3 --- Cartilage degradation --- p.210 / Chapter 7.3 --- Discussions --- p.237 / Chapter Chapter 8 --- Conclusions --- p.239 / References --- p.243