Biomedical subjects

Gary S Firestein

Publications and source records attributed to Gary S Firestein.

58 records · Page 4Linked to original sources

PubMed2002

Regulation of joint destruction and inflammation by p53 in collagen-induced arthritis.

The role of the tumor suppressor p53 as a key regulator of inflammation was examined in murine collagen-induced arthritis (CIA), a model of rheumatoid arthritis. Wild-type DBA/1 mice develop progressive arthritis in this model, in which p53 expression and apoptosis are evident in the synovial cells. In contrast, the joints of p53(-/-) DBA/1 animals with CIA showed increased severity of arthritis using clinical and histological scoring methods with almost no apoptosis. Consistent with this, collagenase-3 expression and cytokine production (interleukin-1 and interleukin-6) in the joints of p53(-/-) mice with CIA were significantly greater than in wild-type mice. Anti-collagen antibody titers, however, were not different. Therefore, p53 expression occurs during inflammation and acts to suppress local inflammatory responses. Because mutations in p53 have been described in the synovial membrane of rheumatoid arthritis patients, the loss of p53 function in synoviocytes or other cells in the joint because of dominant-negative mutations might contribute to invasion and destruction of the joint in this disease.

Animals↗

PubMed2002

The genetics of the target tissue in rheumatoid arthritis.

The genetic mechanisms that are complementary in predisposing and then establishing disease are yet to be fully elucidated. During a lifetime, the genetic composition of the host is not only hereditary but undergoes rearrangements, integrations, and more subtle single-base pair alterations. These changes can be inconsequential or lead to aberrant and deleterious pathologic changes. In a complex multifactorial disease such as RA, the relative roles of the dynamic versus germline elements of the disease have yet to be fully determined. Further studies of large populations are likely to segregate out factors affecting specific ethnic, clinical, and genetic subgroups.

Arthritis, Rheumatoid↗

PubMed2002

Tumor necrosis factor-alpha, an initiator, and etanercept, an inhibitor of cochlear inflammation.

OBJECTIVES/HYPOTHESIS: The inner ear rapidly mounts an immune response that can lead to cochlear degeneration and permanent hearing loss. Identification of proinflammatory cytokine expression during the initiation of the response should lead to rational therapeutic strategies that block the response, reducing damaging sequelae. STUDY DESIGN: A cochlear immune response to keyhole limpet hemocyanin (KLH) injected into the inner ear or subarachnoid space of sensitized animals was created. Etanercept was administered to a group of animals to blunt the immune response. METHODS: Cochleae were immunoassayed for expression of interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6 and evaluated for the amount of cochlear-infiltrated cells. RESULTS: Tumor necrosis factor-alpha and interleukin-1beta were expressed by infiltrated cells shortly after KLH injection. Tumor necrosis factor-alpha was expressed whether the antigen was introduced with or without surgical trauma. Interleukin-1beta was also expressed by the cochlear fibrocytes during the immune response and in surgical control animals, but not after intrathecal injection of antigen. Interleukin-6 expression was minimal during the response. Based on this observation, animals were treated with systemic injection of Etanercept, which reduced cochlear infiltrating cell number and cochlear fibrosis. CONCLUSION: Interleukin-1beta expression is a general cochlear response to trauma, whereas tumor necrosis factor-alpha expression in the infiltrated immunocompetent cells is the cytokine that induces amplification of the response that leads to cochlear disease.

Animals↗

PubMedDate not supplied

Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist.

BACKGROUND: Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant disorder characterised by recurrent episodes of rash, arthralgia, and fever after cold exposure. The genetic basis of this disease has been elucidated. Cryopyrin, the protein that is altered in FCAS, is one of the adaptor proteins that activate caspase 1, resulting in release of interleukin 1. METHODS: An experimental cold challenge protocol was developed to study the acute inflammatory mechanisms occurring after a general cold exposure in FCAS patients and to investigate the effects of pretreatment with an antagonist of interleukin 1 receptor (IL-1Ra). ELISA, real-time PCR, and immunohistochemistry were used to measure cytokine responses. FINDINGS: After cold challenge, untreated patients with FCAS developed rash, fever, and arthralgias within 1-4 h. Significant increases in serum concentrations of interleukin 6 and white-blood-cell counts were seen 4-8 h after cold challenge. Serum concentrations of interleukin 1 and cytokine mRNA in peripheral-blood leucocytes were not raised, but amounts of interleukin 1 protein and mRNA were high in affected skin. IL-1Ra administered before cold challenge blocked symptoms and increases in white-blood-cell counts and serum interleukin 6. INTERPRETATION: The ability of IL-1Ra to prevent the clinical features and haematological and biochemical changes in patients with FCAS indicates a central role for interleukin 1beta in this disorder. Involvement of cryopyrin in activation of caspase 1 and NF-kappaB signalling suggests that it might have a role in many chronic inflammatory diseases. RELEVANCE TO PRACTICE: These findings support a new therapy for a disorder with no previously known acceptable treatment. They also offer insights into the role of interleukin 1beta in more common inflammatory diseases.

Acute Disease↗