Cyclosporin A Decreases Human Macrophage Interleukin‐6 Synthesis at Post‐Transcriptional Level

Abstract

In addition to its well-established effect on T cells, cyclosporin A (CsA) also inhibits inflammatory cytokine production by macrophages. However, little is known about the mechanism of action of CsA on macrophage cytokine production. We measured the effect of CsA on basal and phorbol-myristate-acetate (PMA)-stimulated production of interleukin-6 using the human monocyte cell line U937 differentiated with dimethylsulfoxide (DMSO). Interleukin-6 levels were measured in supernatant and cell lysates using specific enzyme-linked immunosorbent assays. We found that CsA decreases not only IL-6 release but also cytokine synthesis. The concentration of CsA used did not affect either cell viability or proliferation. Three possibilities may be advanced to explain the CsA-due decrease in IL-6 production by macrophages: (a) inhibition of the synthesis of an early common regulatory protein, (b) inhibition of cytokine gene transcription, or (c) modulation of post-transcriptional events. The first possibility was tested by measuring the effect of cycloheximide on the experimental system during the first 3 hours of culture. Although cycloheximide decreased total cytokine synthesis, the pattern of cytokine modulation by CsA persisted. These data suggest that CsA-mediated macrophage cytokine inhibition is not mediated by an early common regulatory protein. To further explore the inhibition mechanism, we measured IL-6 mRNA levels by Northern blot. IL-6 mRNA levels were unaffected by CsA both in resting and PMA-stimulated cells. We conclude that in human macrophages CsA diminishes IL-6 production at post-transcriptional level.

Contractile properties, structure and fiber phenotype of intact and regenerating slow-twitch muscles of mice treated with cyclosporin A

“…The resulting delay in removing cell debris after injury may result in the deposition of calcium, which hampers subsequent phagocytosis. Although the evidence concerning CsA effects on macrophages is not always consistent (for a review, see Losa Garcia et al 1996), observations such as the inhibition of macrophage activation and of cytokine production by these cells and the reduced phagocytosis (see, for example, Thorat et al 1994;Holschermann et al 1996;Wasaki et al 1997;Garcia et al 1999) support our speculation.…”

Modulation of Cell-Mediated Immunity to Suppress High Fat Diet-Induced Obesity and Insulin Resistance

“…It reduces the activity of the immune system by interfering with the activity and growth of T cells (5). Previous reports show that CsA decreased IL-6 synthesis at the post-transcriptional level in human macrophages (6). In addition, previous studies have shown that CsA treatment reduces inflammation by down-regulating production of several inflammatory cytokines (6–8).…”

Interleukin-6 Polymorphism: A Genetic Risk Factor for Cardiac Transplant Related Coronary Vasculopathy?

“…IL-6 levels are reduced by steroids 49,50 and cyclosporine. 51 Immunosuppressed low IL-6 producers may have very low IL-6 levels and, paradoxically, may be more prone to vascular injury.…”