PMID- 28065589
OWN - NLM
STAT- MEDLINE
DCOM- 20170615
LR  - 20181113
IS  - 1096-0007 (Electronic)
IS  - 0014-4835 (Print)
IS  - 0014-4835 (Linking)
VI  - 155
DP  - 2017 Feb
TI  - PERK and XBP1 differentially regulate CXCL10 and CCL2 production.
PG  - 1-14
LID - S0014-4835(17)30008-8 [pii]
LID - 10.1016/j.exer.2017.01.002 [doi]
AB  - Inflammation plays a key role in the pathogenesis of many retinal degenerative 
      diseases related with photoreceptor dysfunction/degeneration. However the 
      involvement of photoreceptor cells in inflammatory reactions is largely unknown 
      as they are not considered as inflammatory cells. In this study, we assessed 
      whether photoreceptor cells can produce CCL2 and CXCL10, two important players in 
      inflammation during endoplasmic reticulum (ER) stress. After photoreceptor 661 W 
      cells were treated with ER stress inducer thapsigargin (TG), induction of ER 
      stress increased CXCL10 and CCL2 expression at both mRNA and protein levels, 
      which was significantly blocked by an ER stress blocker 4-phenylbutyrate. ER 
      stress contains three pathways: PERK, ATF6 and IRE1alpha. Knockdown of PERK 
      attenuated TG-induced CXCL10 and CCL2 mRNA expression, associated with 
      significant decreases in phosphorylation of NF-kappaB RelA and STAT3. In contrast to 
      PERK, knockdown of XBP1, which is activated by IRE1alpha-mediated splicing, robustly 
      enhanced TG-induced CXCL10 and CCL2 expression and phosphorylation of NF-kappaB RelA 
      and STAT3. Blockade of NF-kappaB or STAT3 markedly diminished TG-induced CXCL10 and 
      CCL2 expression. The specific roles of PERK and XBP1 in CXCL10 and CCL2 
      expression were further investigated by treating photoreceptor cells with 
      advanced glycation end products (AGE) and high glucose (HG), two of the major 
      contributors to diabetic complications. Similarly, AGE and HG induced CXCL10 and 
      CCL2 expression in which PERK was a positive regulator while XBP1 was a negative 
      regulator. These studies suggest that photoreceptors may be involved in retinal 
      inflammation by expressing chemokines CXCL10 and CCL2. PERK and IRE1alpha/XBP1 in the 
      unfolded protein response differentially regulate the expression of CXCL10 and 
      CCL2 likely through modulation of ER stress-induced NF-kappaB RelA and STAT3 
      activation.
CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
FAU - Zhu, Shuang
AU  - Zhu S
AD  - Research Center for Neurology, Xuzhou Medical University, Xuzhou, Jiangsu, China; 
      Department of Ophthalmology and Visual Sciences, The University of Texas Medical 
      Branch, Galveston, TX, USA.
FAU - Liu, Hua
AU  - Liu H
AD  - Center for Biomedical Engineering, The University of Texas Medical Branch, 
      Galveston, TX, USA.
FAU - Sha, Haibo
AU  - Sha H
AD  - Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
FAU - Qi, Ling
AU  - Qi L
AD  - Department of Molecular and Integrative Physiology, University of Michigan 
      Medical School, Ann Arbor, USA.
FAU - Gao, Dian-Shuai
AU  - Gao DS
AD  - Research Center for Neurology, Xuzhou Medical University, Xuzhou, Jiangsu, China. 
      Electronic address: gds@xzmc.edu.cn.
FAU - Zhang, Wenbo
AU  - Zhang W
AD  - Department of Ophthalmology and Visual Sciences, The University of Texas Medical 
      Branch, Galveston, TX, USA; Neuroscience and Cell Biology, The University of 
      Texas Medical Branch, Galveston, TX, USA. Electronic address: we2zhang@utmb.edu.
LA  - eng
GR  - R01 EY022694/EY/NEI NIH HHS/United States
GR  - R01 GM113188/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170105
PL  - England
TA  - Exp Eye Res
JT  - Experimental eye research
JID - 0370707
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokine CXCL10)
RN  - 0 (Cxcl10 protein, mouse)
RN  - 0 (Cytokines)
RN  - 0 (X-Box Binding Protein 1)
RN  - 0 (Xbp1 protein, mouse)
RN  - 63231-63-0 (RNA)
RN  - EC 2.7.11.1 (PERK kinase)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Chemokine CCL2/biosynthesis/*genetics
MH  - Chemokine CXCL10/biosynthesis/*genetics
MH  - Cytokines
MH  - Disease Models, Animal
MH  - Endoplasmic Reticulum Stress/*genetics
MH  - Enzyme-Linked Immunosorbent Assay
MH  - *Gene Expression Regulation
MH  - Mice
MH  - Mice, Knockout
MH  - Photoreceptor Cells, Vertebrate/cytology/*metabolism
MH  - Polymerase Chain Reaction
MH  - RNA/genetics
MH  - Retinal Degeneration/genetics/metabolism/pathology
MH  - X-Box Binding Protein 1/*metabolism
MH  - eIF-2 Kinase/*metabolism
PMC - PMC5359061
MID - NIHMS846526
OTO - NOTNLM
OT  - Chemokine
OT  - ER stress
OT  - NF-kappaB
OT  - Photoreceptor
OT  - STAT3
EDAT- 2017/01/10 06:00
MHDA- 2017/06/16 06:00
PMCR- 2018/02/01
CRDT- 2017/01/10 06:00
PHST- 2016/08/24 00:00 [received]
PHST- 2016/12/11 00:00 [revised]
PHST- 2017/01/04 00:00 [accepted]
PHST- 2017/01/10 06:00 [pubmed]
PHST- 2017/06/16 06:00 [medline]
PHST- 2017/01/10 06:00 [entrez]
PHST- 2018/02/01 00:00 [pmc-release]
AID - S0014-4835(17)30008-8 [pii]
AID - 10.1016/j.exer.2017.01.002 [doi]
PST - ppublish
SO  - Exp Eye Res. 2017 Feb;155:1-14. doi: 10.1016/j.exer.2017.01.002. Epub 2017 Jan 5.