Article Text

PDF

173 INTERLEUKIN-1 ALPHA ACTIVITY IN NECROTIC ENDOTHELIAL CELLS IS DYNAMICALLY CONTROLLED BY INTRACELLULAR INTERLEUKIN-1 RECEPTOR 2
  1. L Burzynski,
  2. M Humphry,
  3. M Bennett,
  4. M Clarke
  1. University of Cambridge

    Abstract

    Inflammation is a key driver of both atherosclerosis and graft rejection. Interleukin-1 alpha (IL-1α), a powerful cytokine that activates both innate and adaptive immunity, induces vessel inflammation after release from necrotic vascular smooth muscle cells (VSMCs). Similarly, IL-1α released from damaged endothelial cells (ECs) during vessel transplant drives allogeneic graft rejection. Therefore it is important to understand how IL-1α activity is controlled after EC necrosis, and how this affects atherosclerosis and graft rejection.

    We investigated IL-1α activity in control and TNFα or IL-1β stimulated ECs. Necrotic ECs have much lower IL-1α activity than VSMCs, but show comparable levels to other cell-types, even though they contain a tenth of the IL-1α. Following TNFα or IL-1β stimulation IL-1α activity in necrotic ECs is increased up to 8-fold without alteration to IL-1α protein level. Together, these data imply that IL-1α activity is controlled independently of protein level in necrotic ECs.

    Immunofluorescence and proximity ligation assays show a cytosolic association between IL-1α and IL-1R2, which is known to inhibit IL-1αactivity. Following TNFα or IL-1β stimulation necrotic EC lysates contain more calpain cleaved IL-1α, which shows increased activity. In addition, IL-1R2 in stimulated lysates is less able to protect exogenously added pro-IL-1α,suggesting TNFα or IL-1β dissociates IL-1α from IL-1R2, subsequently allowing calpain to cleave and increase IL-1α activity upon necrosis.

    We conclude that necrotic EC-derived IL-1α is regulated by binding to cytosolic IL-1R2, and that TNFα and IL-1 modulate this protective mechanism to license IL-1α after necrosis. These and previous data suggest that necrotic ECs may play an important role in vessel wall inflammation during graft rejection, and may also drive atherosclerosis.

    Statistics from Altmetric.com

    Request permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.