PMID- 26786104
OWN - NLM
STAT- MEDLINE
DCOM- 20161103
LR  - 20210205
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 291
IP  - 17
DP  - 2016 Apr 22
TI  - Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid 
      Polypeptide (IAPP) Aggregates.
PG  - 8908-17
LID - 10.1074/jbc.M115.712455 [doi]
AB  - Aggregation of islet amyloid polypeptide (IAPP) contributes to beta cell 
      dysfunction in type 2 diabetes and islet transplantation. Like other 
      amyloidogenic peptides, human IAPP induces macrophage IL-1beta secretion by 
      stimulating both the synthesis and processing of proIL-1beta, a pro-inflammatory 
      cytokine that (when chronically elevated) impairs beta cell insulin secretion. We 
      sought to determine the specific mechanism of IAPP-induced proIL-1beta synthesis. 
      Soluble IAPP species produced early during IAPP aggregation provided a 
      Toll-like-receptor-2- (TLR2-) dependent stimulus for NF-kappaB activation in HEK 293 
      cells and bone marrow-derived macrophages (BMDMs). Non-amyloidogenic rodent IAPP 
      and thioflavin-T-positive fibrillar amyloid produced by human IAPP aggregation 
      failed to activate TLR2. Blockade of TLR6 but not TLR1 prevented hIAPP-induced 
      TLR2 activation, consistent with stimulation of a TLR2/6 heterodimer. TLR2 and 
      its downstream adaptor protein MyD88 were required for IAPP-induced cytokine 
      production by BMDMs, a process that is partially dependent on autoinduction by 
      IL-1. BMDMs treated with soluble but not fibrillar IAPP provided a TLR2-dependent 
      priming stimulus for ATP-induced IL-1beta secretion, whereas late IAPP aggregates 
      induced NLRP3-dependent IL-1beta secretion by LPS-primed macrophages. Moreover, 
      inhibition of TLR2 and depletion of islet macrophages prevented up-regulation of 
      Il1b and Tnf expression in human IAPP-expressing transgenic mouse islets. These 
      data suggest participation by both soluble and fibrillar aggregates in 
      IAPP-induced islet inflammation. IAPP-induced activation of TLR2 and secretion of 
      IL-1 may be important therapeutic targets to prevent amyloid-associated beta cell 
      dysfunction.
CI  - (c) 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Westwell-Roper, Clara
AU  - Westwell-Roper C
AD  - From the Departments of Pathology & Laboratory Medicine and.
FAU - Denroche, Heather C
AU  - Denroche HC
AD  - Surgery, Child & Family Research Institute, University of British Columbia, 
      Vancouver, British Columbia V5Z 4H4, Canada.
FAU - Ehses, Jan A
AU  - Ehses JA
AD  - Surgery, Child & Family Research Institute, University of British Columbia, 
      Vancouver, British Columbia V5Z 4H4, Canada.
FAU - Verchere, C Bruce
AU  - Verchere CB
AD  - From the Departments of Pathology & Laboratory Medicine and Surgery, Child & 
      Family Research Institute, University of British Columbia, Vancouver, British 
      Columbia V5Z 4H4, Canada bverchere@cfri.ca.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160119
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Carrier Proteins)
RN  - 0 (IL1B protein, human)
RN  - 0 (IL1B protein, mouse)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Islet Amyloid Polypeptide)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (NLRP3 protein, human)
RN  - 0 (Nlrp3 protein, mouse)
RN  - 0 (Toll-Like Receptors)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Carrier Proteins/genetics/immunology
MH  - HEK293 Cells
MH  - Humans
MH  - *Immunity, Innate
MH  - Insulin-Secreting Cells/*immunology/pathology
MH  - Interleukin-1beta/genetics/immunology
MH  - Islet Amyloid Polypeptide/genetics/*immunology
MH  - Lipopolysaccharides/pharmacology
MH  - Mice
MH  - Mice, Knockout
MH  - NLR Family, Pyrin Domain-Containing 3 Protein
MH  - Protein Aggregation, Pathological/genetics/*immunology/pathology
MH  - Toll-Like Receptors/genetics/immunology
MH  - Tumor Necrosis Factor-alpha/genetics/immunology
PMC - PMC4861460
OTO - NOTNLM
OT  - amyloid
OT  - diabetes
OT  - innate immunity
OT  - protein aggregation
OT  - toll-like receptor (TLR)
EDAT- 2016/01/21 06:00
MHDA- 2016/11/04 06:00
PMCR- 2017/04/22
CRDT- 2016/01/21 06:00
PHST- 2015/12/24 00:00 [received]
PHST- 2016/01/21 06:00 [entrez]
PHST- 2016/01/21 06:00 [pubmed]
PHST- 2016/11/04 06:00 [medline]
PHST- 2017/04/22 00:00 [pmc-release]
AID - S0021-9258(20)41093-2 [pii]
AID - M115.712455 [pii]
AID - 10.1074/jbc.M115.712455 [doi]
PST - ppublish
SO  - J Biol Chem. 2016 Apr 22;291(17):8908-17. doi: 10.1074/jbc.M115.712455. Epub 2016 
      Jan 19.