Faculty Bibliography

Because the mechanisms of Helicobacter pylori-induced gastric injury are incompletely understood, we examined the hypothesis that H. pylori induces matrix metalloproteinase-1 (MMP-1) secretion, with potential to disrupt gastric stroma. We further tested the role of CagA, an H. pylori virulence factor, in MMP-1 secretion. Co-incubation of AGS cells with Tx30a, an H. pylori strain lacking the cagA virulence gene, stimulated MMP-1 secretion, confirming cagA-independent secretion. Co-incubation with strain 147C (cagA(+)) resulted in CagA translocation into AGS cells and increased MMP-1 secretion relative to Tx30a. Transfection of cells with the recombinant 147C cagA gene also induced MMP-1 secretion, indicating that CagA can independently stimulate MMP-1 secretion. Co-incubation with strain 147A, containing a cagA gene that lacks an EPIYA tyrosine phosphorylation motif, as well as transfection with 147A cagA, yielded an MMP-1 secretion intermediate between no treatment and 147C, indicating that CagA tyrosine phosphorylation regulates cellular signaling in this model system. H. pylori induced activation of the MAP kinase ERK, with CagA-independent (early) and dependent (later) components. MEK inhibitors UO126 and PD98059 inhibited both CagA-independent and -dependent MMP-1 secretion, whereas p38 inhibition enhanced MMP-1 secretion and ERK activation, suggesting p38 negative regulation of MMP-1 and ERK. These data indicate H. pylori effects on host epithelial MMP-1 expression via ERK, with p38 playing a potential regulatory role

Cytokines such as TNF-alpha and IL-1beta play key roles in driving the inflammation and synovial cell proliferation that characterize rheumatoid arthritis (RA) joint destruction. It is, therefore, not surprising that therapies for RA have targeted these cytokines. While blockade of TNF-alpha or IL-1beta has been efficacious for many patients with RA, adequacy and maintenance of response are not universal, and increased risk of adverse events such as infection and malignancy remains a concern. Therefore, new targets in the treatment of RA continue to be examined. As interleukin-6 (IL-6) has been implicated in the pathogenesis of RA, blockade of its activity is of both scientific and clinical interest. The basic biology of IL-6, the in vitro animal data supporting its role in RA, and the human trials to date that test the possible efficacy of IL-6-directed therapy for RA are reviewed

Over the past decade, significant advances have been made regarding the pathogenesis, clinical implications, and treatment of hyperuricemia. While physicians have understood for at least a century that uric acid causes gout, we are now beginning to address the question of why hyperuricemia exists and the mechanisms by which uric acid acts to stimulate inflammation. This review focuses on (1) previously unknown biological roles of uric acid; (2) why the loss of the uricase gene and resultant hyperuricemia may have provided an evolutionary advantage to primates and, in particular, to humans; (3) the molecular effects of uric acid on inflammatory cells; and (4) novel antihyperuricemic agents currently under study

Ras is a GTP-binding protein that plays multiple important roles in cell activation, including proliferative and inflammatory responses. Ras regulation is complex and depends upon post-translational processing, organelle-specific localization and the activation/deactivation of Ras by a number of regulatory molecules. Ras activation in T lymphocytes demonstrates unique features, including its dependence on the T cell receptor and the ability of Ras to signal from both the plasma membrane and the Golgi. Abnormalities of Ras expression, activation and signaling pathways in T lymphocytes appear to play important roles in the development of autoimmunity in general, and systemic lupus erythematosus in particular. In this manuscript, we review the basic biology of Ras in T lymphocytes, and the ways in which T lymphocyte Ras abnormalities may contribute to the development of a lupus phenotype

OBJECTIVE: To determine whether protein prenylation (farnesyl/geranylgeranylation) regulates matrix metalloproteinase (MMP) secretion from rheumatoid arthritis (RA) synovial fibroblasts (RASFs), and whether MMP-1 secretion can be regulated by statins or prenyltransferase inhibitors via effects mediated by ERK, JNK, and NF-kappaB. METHODS: RASFs obtained from patients during elective knee replacement surgery were assessed by immunoblotting and/or enzyme-linked immunosorbent assay for secretion of MMP-1 and MMP-13 in the presence of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), statins, the farnesyl transferase (FT) inhibitor FTI-276 and geranylgeranyl transferase inhibitor GGTI-298, and prenyl substrates (farnesyl pyrophosphate [FPP] and geranylgeranyl pyrophosphate [GGPP]). Activities of JNK and ERK were determined by phosphoimmunoblotting, and NF-kappaB activation was determined by nuclear translocation of the p65 component. RESULTS: FTI-276, but not statins, inhibited RASF secretion of MMP-1, but not MMP-13, following induction with TNFalpha (P = 0.0007) or IL-1beta (P = 0.006). Loading RASFs with FPP to promote farnesylation enhanced MMP-1 secretion. FTI-276 inhibited activation of JNK (P < 0.05) and NF-kappaB (P = 0.02), but not ERK. In contrast, GGTI-298 enhanced, while GGPP inhibited, MMP-1 secretion. FTI-276 and GGTI-298 together had no effect on MMP-1 secretion. Stimulation of RASFs with TNFalpha or IL-1beta led to increased expression and activity of FT. CONCLUSION: Protein farnesylation is required for expression and secretion of MMP-1 from RASFs, via effects on JNK and NF-kappaB. The ability of cytokines to stimulate the expression and activity of FT suggests that FT may be increased in the rheumatoid joint. In contrast, geranylgeranylation down-regulates MMP-1 expression. Statins simultaneously inhibit farnesylation and geranylgeranylation, and in consequence do not inhibit MMP-1 secretion. The ability of FTI-276 to inhibit MMP-1 secretion suggests a potential therapeutic strategy in RA

After several decades of senescence, the twin fields of hyperuricemia and gout have again regained attention in both the scientific and clinical spheres, and this review highlights several recent advancements. Specifically, we review newly discovered mechanisms of uric acid-induced inflammation, uric acid's putative role as a 'danger signal' in innate immunity, the possible link between hyperuricemia and cardiovascular disease, and evolutionary evidence suggesting that hyperuricemia conferred a survival advantage in primates (when the gene for uricase was lost) several million years ago. Finally, we provide an overview of the current approach to gout, as well as what treatments are on the horizon