Regulation of the balance of cytokine production and the signal transducer and activator of transcription (STAT) transcription factor activity by cytokines and inflammatory synovial fluids.

Abstract

SummaryThe balance between type 1 and 2 T helper cell cytokine production plays an important role in several animal models ofautoimmunity, and skewed patterns of cytokine expression have been described in human inflammatory diseases . Many cytokines activate signal transducer and activation of transcription (STAT) transcription factors, which, in turn, activate transcription ofinflammatory effector genes. We used mononuclear cell priming cultures and inflammatory synovial fluids (SFs) derived from arthritis patients to examine the regulation of cytokine production and STAT activity by an inflammatory synovial microenvironment. Exposure to SFs during priming resulted in an 81% inhibition of interferon (IFN) -'y, but not interleukin (IL) 4, production by effector cells generated in priming cultures . SF suppression was mediated by IL-4 and IL-10 and inhibition ofIL-12 expression, and it was reversed in a dominant fashion by exogenous IL-12 . SFs blocked the sustained activity of transcription factor Statl, but not Stat3, during the priming period, and Statl activity was differentially regulated by cytokines in parallel with their positive or negative regulation of IFN-y production . Active Stat3, but not Statl, was detected in cells from inflamed joints . These results suggest a role for altered balance of Statl and Stat3 transcriptional activity in the regulation of T cell differentiation and in the pathogenesis ofinflammatory synovitis .

Borrelia burgdorferi-Induced Expression of Matrix Metalloproteinases from Human Chondrocytes Requires Mitogen-Activated Protein Kinase and Janus Kinase/Signal Transducer and Activator of Transcription Signaling Pathways

“…STAT proteins are critical in mediating intracellular effects of various cytokines and are implicated in the expression of many inflammatory effector genes. Active STAT-3 has been detected in cells from inflamed joints (30), and synovial fluids from rheumatoid arthritis patients can activate STAT-3 but not STAT-1 in monocytes (24). Similarly, we found that B. burgdorferi infection resulted in activation of STAT-3 and STAT-6, but not STAT-1.…”

The JAK/STAT pathway in rheumatoid arthritis: Pathogenic or protective?

“…The first reports of JAK/STAT activation in RA described constitutive STAT-3 DNA binding activity in freshly isolated RA synovial fluid (SF) mononuclear cells, and showed that soluble factors contained in RA SFs effectively activated STAT-3 in control human monocytes (12,13). IL-6 was the major STAT-3-activating factor present in RA SFs.…”

Local activation of STAT‐1 and STAT‐3 in the inflamed synovium during zymosan‐induced arthritis: Exacerbation of joint inflammation in STAT‐1 gene–knockout mice

“…Studies on activation of STATs in RA synovial fluid (SF) cells have yielded conflicting results. Activated STAT-3 has been found in SF cells from RA patients (5). Furthermore, SF from RA patients has been shown to induce STAT-3 activation in monocytes (6); this activity could be blocked by neutralization of IL-6.…”