Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 9, Pages 3298-3303Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0511233103
Keywords
autoimmune; inflammation; tumor necrosis factor
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Funding
- NCI NIH HHS [P30 CA046934, CA-046934] Funding Source: Medline
- NHLBI NIH HHS [HL-68743, P01 HL068743] Funding Source: Medline
- NIAID NIH HHS [AI-15614, R01 AI015614, R56 AI015614] Funding Source: Medline
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IL-32 is a recently discovered cytokine that induces TNF alpha, IL-1 beta, IL-6, and chemokines. We investigated whether IL-32 is expressed in the synovia of patients with rheumatoid arthritis (RA) and studied associations with disease severity and the presence of other cytokines. Immunohistochemistry revealed that IL-32 is highly expressed in RA synovial tissue biopsies, whereas IL-32 was not observed in synovial tissues from patients with osteoarthritis. Moreover, in synovial biopsies from 29 RA patients with active disease, the level of IL-32 staining correlated with erythrocyte sedimentation rate, a marker of systemic inflammation (R = 0.63 and P < 0.0003). Synovial staining of IL-32 also correlated with indices of synovial inflammation (R = 0.80 and P < 0.0001) as well as synovial presence of TNFa (R = 0.68 and P < 0.004), IL-10 (R = 0.79 and P < 0.0001), and IL-18 (R = 0.82 and P < 0.001). IL-32 was a potent inducer of prostaglandin E-2 release in mouse macrophages and human blood monocytes, an important property for inflammation. After the injection of human IL-32 gamma into the knee joints of naive mice, joint swelling, with pronounced influx of inflammatory cells and cartilage damage, was observed. In TNF alpha-deficient mice, IL-32-driven joint swelling was absent and cell influx was markedly reduced, but loss of proteoglycan was unaffected, suggesting that IL-32 activity is, in part, TNF alpha-dependent. IL-32, strongly associated with TNFa, IL-1 beta, and IL-18, appears to play a role in human RA and may be a novel target in autoimmune diseases.
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