Significant morbidity and mortality can be attributed to inflammatory diseases; therefore, a greater understanding of the mechanisms involved in the progression of inflammation is crucial. Here, we demonstrate that p21 (WAF1/CIP1) , an established suppressor of cell cycle progression, is a inhibitor of IL-1b synthesis in macrophages. Mice deficient in p21 (p21 À/À ) display increased susceptibility to endotoxic shock, which is associated with increased serum levels of IL-1b. Administration of IL-1 receptor antagonist reduces LPS-induced lethality in p21 À/À mice. Analysis of isolated macrophages, which are one of the central producers of IL-1b, reveals that deficiency for p21 led to more IL-1b mRNA and pro-protein synthesis following TLR ligation. The increase in IL-1b pro-protein is associated with elevated secretion of active IL-1b by p21 À/À macrophages. siRNA-mediated knockdown of p21 in human macrophages results in increased IL-1b secretion as well. A peptide mapping strategy shows that the cyclin-dependent-kinase (CDK)-binding domain of p21 is sufficient to reduce the secretion of IL-1b by p21 À/À macrophages. These data suggest a novel role for p21 and specifically for the CDK-binding domain of p21 (WAF1/CIP1) in inhibiting inflammation. IntroductionThe pleiotropic cytokine IL-1b is required for the progression of numerous inflammatory disorders [1]. As key components of the innate immune response, monocytes and macrophages play an important role in the initiation and/or progression of inflammatory disease, largely through secretion of IL-1b, which contributes significantly to pathogenesis. Current treatments for diseases such as rheumatoid arthritis, gout, and periodic fever syndromes include the IL-1 receptor antagonist anakinra (Kineret s , Amgen) SHORT COMMUNICATIONÃ These authors contributed equally to this work. 820[2]; yet this therapy is ineffective in a cohort of patients [3]. Therefore, a better understanding of the mechanisms by which IL-1b production is regulated remains crucial for the development of new therapies to treat inflammatory diseases.Here, we investigate the role that p21 (WAF1/CIP1) (p21) plays in the production of IL-1b and development of inflammatory disease. As a member of the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors, p21 induces blockade of cell cycle progression via inhibition of the activity of CDK/cyclin complexes as well as that of proliferating cell nuclear antigen (PCNA) [4]. p21 binds to CDK and cyclins through two distinct domains on the N-terminus and to PCNA via its C-terminus [5]. Mice deficient in p21 show no developmental or reproductive abnormalities, although the mice display sensitivity to radiation [6] and develop a form of lupus-like disease [6][7][8]. Furthermore, a paucity of p21 expression is observed in synovial tissue from rheumatoid arthritis patients compared with osteoarthritis controls [9]. Because of the implication of p21 in the pathogenesis of lupus and rheumatoid arthritis and the importance of IL-1b in these and other inflamm...

Mycobacterial spindle cell pseudotumor (MSP) is a rare benign spindle cell lesion containing acid-fact mycobacteria. These lesions are most commonly identified in the lymph nodes, skin, spleen, or bone marrow of immunocompromised patients and only rarely involve the lungs. We report 3 cases of pulmonary MSP, which include 2 patients who are known to be HIV-positive. The histopathological diagnosis of MSP in the lung lends itself to many challenges due to its rare incidence and its spindled tumor-like appearance. The differential diagnosis is broad and includes both benign and malignant entities. We highlight the importance of the clinical context in which these lesions typically present and the morphologic spectrum of features seen, and we offer a practical approach to the workup of pulmonary mycobacterial pseudotumor. Appropriate recognition of this entity should lead to an accurate diagnosis of a treatable benign condition despite the clinical presentation often favoring malignancy.

We have previously reported that intratumoral injection of VRX-007—an Ad5-based vector overexpressing ADP (Adenovirus Death Protein)—can suppress the growth of subcutaneous HaK (hamster renal cancer) tumors. VRX-007 replication and tumor growth inhibition are enhanced when the hamsters are immunosuppressed by a high dose of cyclophosphamide (CP), an immunosuppressive and chemotherapeutic agent. Here we report that continuous immunosuppression with CP was not required for increased oncolytic activity of VRX-007 because short-term dosing or continuous dosing with the drug yielded similar antitumor results. Prolonged viral replication was found only in animals on continuous CP treatment. We used 007-Luc, a replication-competent, luciferase-expressing vector similar to VRX-007 to investigate the replication of the vector over time. Tumor growth inhibition was similar in hamsters given CP treatment either one week before or one week after 007-Luc injection, which suggests that CP exerts its antitumor efficacy independently of vector therapy. 007-Luc did not spread far from the inoculation site, even in immunosuppressed, CP-treated animals. Our results indicate that the enhanced effectiveness that is produced by the combination of VRX-007 and CP therapies is due to their two independent mechanisms and that they do not have to be given simultaneously for the improved outcome shown.

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