Because interferon-gamma (IFN-gamma) selectively inhibits collagen gene expression, we hypothesized that expression of IFN-gamma cDNA in fibroblasts might be a useful strategy to inhibit the development of fibrosis. A replication-deficient E1-, E3- adenovirus vector encoding murine IFN-gamma (AdCM VmIFN gamma) was constructed. Infection of murine fibroblasts with AdCM VmIFN gamma in vitro was well tolerated. The results showed that IN F-gamma mRNA was expressed in infected cells, and as much as 17.7 ng of mIFN-gamma/10(6) cells was secreted into culture supernatants. Steady-state levels of alpha 1 (I) procollagen mRNA were decreased by 90% in infected cells compared to uninfected cells. The inhibition of collagen mRNA expression was partially abrogated with a neutralizing anti-mIFN-gamma antibody. Secretion of total collagen by AdCM VmIFN gamma-infected fibroblasts was decreased by 60% compared to uninfected cells. Induction cells. Induction of cytokine responsive gene-2 expression in AdCM VmIFN gamma-infected cells demonstrated that suppression of collagen production was a selective response. The results suggest a novel strategy of cytokine gene transfer and expression for the treatment of fibrotic lung diseases.

Adenoviridae↗

PubMedDate not supplied

Lipoxin A4 counteracts synergistic activation of human fibroblast-like synoviocytes.

Excessive production of interleukin-6 (IL-6) and metalloproteinases (MMPs) have been implicated in the pathogenesis of rheumatoid arthritis. Lipoxin A4 (LXA4) and transforming growth factor beta 2 (TGF-beta 2), mediators with potential anti-inflammatory activities, were tested to determine how they affect IL-1 beta-dependent release of IL-6 and MMPs in human fibroblast like synoviocytes. The results showed dramatic differences between the mediators: TGF-beta 2 acted synergistically with IL-1 beta to stimulate IL-6 protein levels, whereas LXA4 inhibited IL-6 expression in dose- and time-dependent manner. Inhibition, by LXA4 was abrogated when cells were pre-incubated with antibody against the LXA4R whereas TGF-beta 2 by itself had no significant effect on IL-6 or MMP levels. LXA4, at nanomolar concentrations, altered the MMP-1 and MMP-3 expression levels of IL-1 beta and TGF-beta 2 stimulated fibroblast like synoviocytes at 5 days. Furthermore, IL-1 beta and TGF-beta 2 up-regulated LXA4R mRNA. These results demonstrate, for the first time, that LXA4Rs mediate the effects of LXA4 on inflammatory responses after combined stimulation of human fibroblast like synoviocytes with IL-1 beta and TGF-beta 2. These activities might constitute an important mechanism by which LXA4 regulates human synovial fibroblast activation.

Cells, Cultured↗

PubMedDate not supplied

Opposing regulation of interleukin-8 and NF-kappaB responses by lipoxin A4 and serum amyloid A via the common lipoxin A receptor.

Lipoxin A4 (LXA4) is a potent eicosanoid that inhibits IL-1beta-induced activation of human fibroblast like synoviocytes (FLS) via the ALX4 receptor. Serum amyloid A (SAA) is an acute phase reactant with cytokine-like properties. SAA has been shown to bind the same seven transmembrane G protein-coupled receptor ligated by LXA4. Here we compared the inflammatory responses of lipid (LXA4) and peptide (SAA) ligands in human FLS via the shared ALX, and characterized their downstream signaling. LXA4 induced stimulation of tissue inhibitors of metalloproteinase-2, whereas SAA induced interleukin-8 and matrix metalloproteinase-3 production. SAA up-regulated NF-kappaB and AP-1 DNA binding activity, while LXA4 markedly inhibited these responses after IL-1beta stimulation. A human IL-8 promoter luciferase construct was transfected into CHO cells stably expressing ALXR in order to determine the role of NF-kappaB and/or AP-1 in the regulation of IL-8 gene expression. The NF-kappaB pathway proved to be the preeminent for the biological responses elicited by both ligands. These findings suggest that two endogenous molecules, targeting a common receptor, could participate in the pathogenesis of inflammatory arthritis by differentially regulating inflammatory responses in tissues expressing the ALXR.

Amyloid↗

PubMedDate not supplied

Ibuprofen to rofecoxib: what does it all mean and what do I do now?

NSAIDs are used throughout the World Health Organization three-step analgesic ladder, and are indicated for pain in all stages of malignancy. Side-effects are common with NSAIDs. Much has been written about NSAIDs and COX, since the discovery of COX-1 and COX-2 isoforms. How do you choose the appropriate NSAID? The choice of NSAID continues to be dependent upon associated gastroduodenal toxicity and the related risk factors of individual patients. Choosing the appropriate NSAID should minimize the likelihood of needing additional medications to manage adverse effects and symptoms caused by the NSAID therapy itself.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMedDate not supplied

Infection with uncommon subgroup Y Neisseria meningitidis in patients with systemic lupus erythematosus.

The association of Neisseria meningitidis infection and systemic lupus erythematosus (SLE) is uncommon. We describe here three patients with SLE who developed disseminated meningococcal disease. Each patient had long-standing SLE and was receiving treatment with prednisone. Furthermore, each patient showed serum hypocomplementemia at the time of the infection. N. meningitidis Group Y, considered to be an organism of relatively low virulence, was isolated from the blood or cerebrospinal fluid in each case. The patients presented with diverse clinical manifestations of meningococcal disease. The relationship of disseminated meningococcal infections to hypocomplementemia in patients with SLE is discussed in light of a review of the literature.

Adolescent↗