Endoplasmic reticulum stress is sufficient for the induction of IL-1β production via activation of the NF-κB and inflammasome pathways.
The mechanisms underlying pathophysiological states such as metabolic syndrome and obesity include endoplasmic reticulum (ER) stress and aberrant inflammatory responses. ER stress results from the accumulation of misfolded proteins during stress conditions. However, the precise mechanisms by which ER stress modulates inflammation remain incompletely understood. In this study, we hypothesized that ER stress alone could represent a sufficient signal for the modulation of inflammasome-dependent cytokine responses. We found that several ER stress-inducing chemicals and the free fatty acid palmitate can trigger IL-1β secretion in various cell types, including monocytic leukemia cells, primary macrophages and differentiated adipocytes. We show that ER stress primes cells for the expression of pro-IL-1β via NF-κB activation and promotes IL-1β secretion. Enhanced IL-1β secretion depended on the activation of the NLRP3 inflammasome through a mechanism involving reactive oxygen species formation and activation of thioredoxin-interacting protein. Chemical chaperone treatment and the pharmacological application of carbon monoxide inhibited IL-1β secretion in response to ER stress. Our results provide a mechanistic link between ER stress and the regulation of inflammation, and suggest that modulation of ER stress may provide a therapeutic opportunity to block progression of low grade chronic inflammation to metabolic syndrome.
School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea.
Sena
S
Kim
School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea.
Yeonsoo
Y
Joe
School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea.
Sun Oh
SO
Jeong
School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea Department of Thoracic and Cardiovascular Surgery, Affiliated Hospital of YanBian University, YanJi, PR China.
Min
M
Zheng
School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea.
Sung Hoon
SH
Back
Department of Pharmacology, School of Medicine, Gyeongsang National University, Jinju, Republic of Korea.
Sang Won
SW
Park
Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Stefan W
SW
Ryter
School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea chung@ulsan.ac.kr.
Hun Taeg
HT
Chung
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D059305:Diet, High-Fat; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D058847:Inflammasomes / Q000187:drug effects / Q000502:physiology*; D053583:Interleukin-1beta / Q000096:biosynthesis*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010168:Palmitates / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013879:Thioredoxins / Q000096:biosynthesis / Q000235:genetics
D002352:Carrier Proteins; D016207:Cytokines; D058847:Inflammasomes; D053583:Interleukin-1beta; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D010168:Palmitates; D017382:Reactive Oxygen Species; C445672:Txnip protein, mouse; D013879:Thioredoxins
ER stress; carbon monoxide; heme oxygenase-1; inflammasome; reactive oxygen species