Interleukin 33 as a mechanically responsive cytokine secreted by living cells

TY - JOUR

T1 - Interleukin 33 as a mechanically responsive cytokine secreted by living cells

AU - Kakkar, Rahul

AU - Hei, Hillary

AU - Dobner, Stephan

AU - Lee, Richard T

PY - 2012/2/24

Y1 - 2012/2/24

N2 - Interleukin 33 (IL-33), a member of the Interleukin 1 cytokine family, is implicated in numerous human inflammatory diseases such as asthma, atherosclerosis, and rheumatoid arthritis. Despite its pathophysiologic importance, fundamental questions regarding the basic biology of IL-33 remain. Nuclear localization and lack of an export signal sequence are consistent with the view of IL-33 as a nuclear factor with the ability to repress RNA transcription. However, signaling via the transmembrane receptor ST2 and documented caspase-dependent inactivation have suggested IL-33 is liberated during cellular necrosis to effect paracrine signaling. We determined the subcellular localization of IL-33 and tracked its intracellular mobility and extracellular release. In contrast to published data, IL-33 localized simultaneously to nuclear euchromatin and membrane-bound cytoplasmic vesicles. Fluorescent pulse-chase fate-tracking documented dynamic nucleo-cytoplasmic flux, which was dependent on nuclear pore complex function. In murine fibroblasts in vitro and in vivo, mechanical strain induced IL-33 secretion in the absence of cellular necrosis. These data document IL-33 dynamic inter-organelle trafficking and release during biomechanical overload. As such we recharacterize IL-33 as both an inflammatory as well as mechanically responsive cytokine secreted by living cells.

AB - Interleukin 33 (IL-33), a member of the Interleukin 1 cytokine family, is implicated in numerous human inflammatory diseases such as asthma, atherosclerosis, and rheumatoid arthritis. Despite its pathophysiologic importance, fundamental questions regarding the basic biology of IL-33 remain. Nuclear localization and lack of an export signal sequence are consistent with the view of IL-33 as a nuclear factor with the ability to repress RNA transcription. However, signaling via the transmembrane receptor ST2 and documented caspase-dependent inactivation have suggested IL-33 is liberated during cellular necrosis to effect paracrine signaling. We determined the subcellular localization of IL-33 and tracked its intracellular mobility and extracellular release. In contrast to published data, IL-33 localized simultaneously to nuclear euchromatin and membrane-bound cytoplasmic vesicles. Fluorescent pulse-chase fate-tracking documented dynamic nucleo-cytoplasmic flux, which was dependent on nuclear pore complex function. In murine fibroblasts in vitro and in vivo, mechanical strain induced IL-33 secretion in the absence of cellular necrosis. These data document IL-33 dynamic inter-organelle trafficking and release during biomechanical overload. As such we recharacterize IL-33 as both an inflammatory as well as mechanically responsive cytokine secreted by living cells.

KW - Adenosine Triphosphate/metabolism

KW - Animals

KW - Cell Nucleus/metabolism

KW - Cytoplasm/metabolism

KW - Gene Transfer Techniques

KW - Humans

KW - Interleukin-33

KW - Interleukins/genetics

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Microtubules/metabolism

KW - Myocytes, Cardiac/cytology

KW - NIH 3T3 Cells

KW - Nuclear Pore/metabolism

KW - Paracrine Communication/physiology

KW - Stress, Mechanical

KW - Stress, Physiological/physiology

U2 - 10.1074/jbc.M111.298703

DO - 10.1074/jbc.M111.298703

M3 - SCORING: Journal article

C2 - 22215666

VL - 287

SP - 6941

EP - 6948

JO - J BIOL CHEM

JF - J BIOL CHEM

SN - 0021-9258

IS - 9

ER -