One of the central functions of cyclin-dependent kinase inhibitors, such as p21, p27, or p16, is to prevent entry into the cell cycle. However, the question remains as to whether they have other functions in the cell. We previously demonstrated that overexpression of p21 in fibroblasts isolated from patients with rheumatoid arthritis decreases the production of proinflammatory molecules. Overexpression of p21 has been also shown to reduce the development of experimental arthritis in mice and rats. To explore the role of endogenous p21 in the development of arthritis, we induced arthritis in p21 ؊/؊ mice using the K/BxN serum transfer model of arthritis. Mice deficient in p21 were more resistant to serum transfer-induced arthritis (K/BxN) than wild-type (wt) control mice. Fewer macrophages were detected in p21 ؊/؊ as compared to wt joints following transfer of K/BxN serum. Chemotaxis assays of bone marrow-derived macrophages from p21 ؊/؊ and wt mice revealed no difference in migration. However, there was a substantial decrease in inflammatory monocytes circulating in peripheral blood and in monocyte precursors in bone marrow of p21 ؊/؊ mice as compared to wt mice. Adoptive transfer of wt bone marrow-derived macrophages into p21 ؊/؊ mice restored the sensitivity to serum transfer-induced arthritis. These data suggest a novel role for p21 in regulating the development and/or differentiation of monocytic populations that are crucial for the induction of inflammatory arthritis.

Objective. Fibroblast-like synoviocytes (FLS) are a major constituent of the hyperplastic synovial pannus that aggressively invades cartilage and bone during the course of rheumatoid arthritis (RA). Fractalkine (FKN/ CX 3 CL1) expression is up-regulated in RA synovium and RA synovial fluid. While RA FLS express the FKN receptor, CX 3 CR1, the pathophysiologic relevance of FKN stimulation of RA FLS is not understood. This study was undertaken to better characterize the relationship between FKN and the RA FLS that both produce it and express its receptor.Methods. RA FLS were subjected to chemotaxis and proliferation assays, Western blotting, enzymelinked immunosorbent assays, and filamentous actin staining to characterize the relationship between FKN and RA FLS.

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The vascular endothelium is a primary target of cadmium (Cd) toxicity, but little is known regarding a potential mechanism whereby Cd may inhibit angiogenesis. Recent findings showing that Cd can disrupt cadherin-mediated cell-cell adhesion suggested that Cd might inhibit angiogenesis by altering the function of VE-cadherin, a molecule that is essential for angiogenesis. To address this issue, endothelial cells (ECs) were exposed to Cd in the presence of serum and subjected to angiogenesisrelated cell migration and tube formation assays. Initial examination of cytotoxicity showed that ECs are rather resistant to the acute cytotoxic effects of Cd even at concentrations up to 1mM. However, 10μM Cd decreased migration of ECs. Cd concentrations of 500nM and greater significantly reduced organization of microvascular ECs into tubes. These antiangiogenic effects were evident even when ECs were preincubated with Cd and then washed to remove free Cd, indicating that Cd acted directly on the cells rather than on the extracellular matrix. Immunolocalization studies showed that Cd caused the redistribution of VE-cadherin from cell-cell contacts. These findings indicate that Cd acts in an angiostatic manner on ECs, and that this effect may involve alterations in the localization and function of VE cadherin.* Abbreviations Cd = cadmium DMSO = dimethylsulfoxide EBM-2 = endothelial basal media-2 EC = endothelial cell EGM-2 = endothelial growth media-2 FBS = fetal bovine serum HMVEC = human dermal microvascular endothelial cell HUVEC = human umbilical vein endothelial cell PMA = phorbol 12-myristate 13-acetate ‡ Corresponding author:

Escherichia coli exhibited increased hydrophobicity and mannose-resistant epithelial cell adherence after growth in the presence of human insulin (2 µU mL¯1 or 200 µUmL¯1 insulin, respectively) with glucose (100 mg dL¯1). Capsule production and hemagglutination were unaffected by insulin and glucose. Chemotactic attraction to glucose as compared to insulin or glucose alone was enhanced by the presence of insulin. Insulin alone (200 µU mL¯1) was a chemorepellent and inhibited flagellar tethering to glass. These findings indicate that human insulin can modulate E. coli's expression of factors associated with pathogenesis in a manner that is modifiable by the presence of glucose.