Regulation of inflammatory mediators by tetracyclines

Attur, Mukundan; Dave, Mandar; Mohandas, Nirupama; Patel, Indravadan R.; Abramson, Steven B.; Amin, Ashok R.

doi:10.1007/978-3-0348-8306-1_13

Cited by 6 publications

(9 citation statements)

References 42 publications

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“…Recently, chondrocytes in the superficial and medial zone in OA cartilage have been reported to be positive for IL-1␤ and TNF-␣ compared with normal cartilage using immunohistologic methods (32). We have also shown functional up-regulation of TNF-␣ and TNF-␣ convertase activity in human OA-and RA-affected cartilage compared with normal (33). Although both IL-1␤ and TNF-␣ are up-regulated in OA cartilage, the precise role of TNF-␣ in cartilage homeostasis remains elusive, although they share many biological activities.…”

Section: Discussionsupporting

confidence: 50%

Functional Genomic Analysis of Type II IL-1β Decoy Receptor: Potential for Gene Therapy in Human Arthritis and Inflammation

Attur

Dave

Leung

et al. 2002

The Journal of Immunology

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Gene expression arrays show that human epithelial cells and human arthritis-affected cartilage lack detectable amounts of mRNA for IL-1 antagonizing molecules: IL-1Ra and IL-1RII, but constitutively express IL-1. Functional genomic analysis was performed by reconstituting human IL-1RII expression in various IL-1RII-deficient cell types to examine its antagonist role using gene therapy approaches. Adenovirus-expressing IL-1RII when transduced into human and bovine chondrocytes, human and rabbit synovial cells, human epithelial cells, and rodent fibroblasts expressed membrane IL-1RII and spontaneously released functional soluble IL-1RII. The IL-1RII+ (but not IL-1RII−) cells were resistant to IL-1β-induced, NO, PGE2, IL-6, and IL-8 production or decreased proteoglycan synthesis. IL-1RII inhibited the function of IL-1 in chondrocytes and IL-1- and TNF-α-induced inflammatory mediators in human synovial and epithelial cells. IL-1RII+ chondrocytes were more resistant to induction of NO and PGE2 by IL-1β compared with IL-1RII− cells incubated with a 10-fold (weight) excess of soluble type II IL-1R (sIL-1RII) protein. In cocultures, IL-1RII+ synovial cells released sIL-1RII, which in a paracrine fashion protected chondrocytes from the effects of IL-1β. Furthermore, IL-1RII+ (but not IL-1RII−) chondrocytes when transplanted onto human osteoarthritis-affected cartilage in vitro, which showed spontaneous release of sIL-1RII for 20 days, inhibited the spontaneous production of NO and PGE2 in cartilage in ex vivo. In summary, reconstitution of IL-1RII in IL-1RII− cells using gene therapy approaches significantly protects cells against the autocrine and paracrine effects of IL-1 at the signaling and transcriptional levels.

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Section: Discussionsupporting

confidence: 50%

Functional Genomic Analysis of Type II IL-1β Decoy Receptor: Potential for Gene Therapy in Human Arthritis and Inflammation

Attur

Dave

Leung

et al. 2002

The Journal of Immunology

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“…Even with this approach, we found significant differences in the amount of PGE 2 produced by untreated non-OA versus OA cartilage specimens after 3 weeks in culture and significant differences in IL-1b production during the first few days of culture. The increased synthesis of IL-1b by chondrocytes from OA cartilage has been previously reported (Attur et al, 1998).…”

Section: Non-oa Versus Oamentioning

confidence: 81%

“…Chondrocytes in OA cartilage, especially those in clonal clusters, are positive for IL-1 immunolabeling (Moos et al, 1999;Tetlow et al, 2001), and produce IL-1b converting enzyme (caspase 1) (Saha et al, 1999) and type I IL-1 receptor (MartelPelletier et al, 1992;Sadouk et al, 1995). Chondrocytes in OA cartilage explants also produce IL-1 (Attur et al, 1998). Thus, OA chondrocytes may be continually exposed to the autocrine and paracrine effects of IL-1 and other inflammatory cytokines at low levels and to higher levels when there is an inflammatory illness elsewhere in the body or when the joint is traumatized.…”

mentioning

confidence: 96%

“…These attributes of pellet cultures make them ideal for studying the long-term effects of IL-1. Because OA cartilage was used in this study and OA chondrocytes have been shown to produce IL-1 during the first 72 h of culture (Attur et al, 1998), spontaneous release of IL-1 and NO was measured in conditioned media collected during a 3-week pretreatment period. After IL-1 and NO had dropped to low levels and sufficient new matrix had been deposited, the pellet cultures were treated with a range of concentrations of IL-1b for 2 weeks.…”

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confidence: 99%

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Development of selective tolerance to interleukin‐1β by human chondrocytes in vitro*

Lee

Tioran

Jansen

et al. 2002

Journal Cellular Physiology

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Interleukin-1 induces release of NO and PGE(2) and production of matrix degrading enzymes in chondrocytes. In osteoarthritis (OA), IL-1 continually, or episodically, acts on chondrocytes in a paracrine and autocrine manner. Human chondrocytes in chondron pellet culture were treated chronically (up to 14 days) with IL-1beta. Chondrons from OA articular cartilage were cultured for 3 weeks before treatment with IL-1beta (0.05-10 ng/ml) for an additional 2 weeks. Spontaneous release of NO and IL-1beta declined over the pretreatment period. In response to IL-1beta (0.1 ng/ml), NO and PGE(2) release was maximal on Day 2 or 3 and then declined to near basal level by Day 14. Synthesis was recovered by addition of 1 ng/ml IL-1beta on Day 11. Expression of inducible nitric oxide synthase (iNOS), detected by immunofluorescence, was elevated on Day 2 and declined through Day 14, which coordinated with the pattern of NO release. On the other hand, IL-1beta-induced MMP-13 synthesis was elevated on Day 3, declined on Day 5, and then increased again through Day 14. IL-1beta increased glucose consumption and lactate production throughout the treatment. IL-1beta stimulated proteoglycan degradation in the early days and inhibited proteoglycan synthesis through Day 14. Chondron pellet cultures from non-OA cartilage released the same amount of NO but produced less PGE(2) and MMP-13 in response to IL-1beta than OA cultures. Like the OA, IL-1beta-induced NO and PGE(2) release decreased over time. In conclusion, with prolonged exposure to IL-1beta, human chondrocytes develop selective tolerance involving NO and PGE(2) release but not MMP-13 production, metabolic activity, or matrix metabolism.

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“…These experiments demonstrated a functional paracrine/autocrine role of TNFα in arthritisaffected cartilage that may depend, in part, on upregulated levels of chondrocyte-derived TACE . TACE is a potential target for pharmacological intervention of TNFα production and therefore arthritis (Newton et al,2002;Attur et al, 2002c).…”

Section: Identification Of Novel Proteases From Human Arthritisaffectmentioning

confidence: 99%

A System Biology Approach to Bioinformatics and Functional Genomics in Complex Human Diseases: Arthritis

Attur

Dave

Tsunoyama³

et al. 2002

Current Issues in Molecular Biology

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Human and other annotated genome sequences have facilitated generation of vast amounts of correlative data, from human/animal genetics, normal and disease-affected tissues from complex diseases such as arthritis using gene/protein chips and SNP analysis. These data sets include genes/proteins whose functions are partially known at the cellular level or may be completely unknown (e.g. ESTs). Thus, genomic research has transformed molecular biology from "data poor" to "data rich" science, allowing further division into subpopulations of subcellular fractions, which are often given an "-omic" suffix. These disciplines have to converge at a systemic level to examine the structure and dynamics of cellular and organismal function.The challenge of characterizing ESTs linked to complex diseases is like interpreting sharp images on a blurred background and therefore requires a multidimensional screen for functional genomics ("functionomics") in tissues, mice and zebra fish model, which intertwines various approaches and readouts to study development and homeostasis of a system. In summary, the post-genomic era of functionomics will facilitate to narrow the bridge between correlative data and causative data by quaint hypothesis-driven research using a system approach integrating "intercoms" of interacting and interdependent disciplines forming a unified whole as described in this review for Arthritis.

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Regulation of inflammatory mediators by tetracyclines

Cited by 6 publications

References 42 publications

Functional Genomic Analysis of Type II IL-1β Decoy Receptor: Potential for Gene Therapy in Human Arthritis and Inflammation

Functional Genomic Analysis of Type II IL-1β Decoy Receptor: Potential for Gene Therapy in Human Arthritis and Inflammation

Development of selective tolerance to interleukin‐1β by human chondrocytes in vitro*

A System Biology Approach to Bioinformatics and Functional Genomics in Complex Human Diseases: Arthritis

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