PMID- 24816367
OWN - NLM
STAT- MEDLINE
DCOM- 20150220
LR  - 20211021
IS  - 1432-0428 (Electronic)
IS  - 0012-186X (Linking)
VI  - 57
IP  - 8
DP  - 2014 Aug
TI  - TLR2/6 and TLR4-activated macrophages contribute to islet inflammation and impair 
      beta cell insulin gene expression via IL-1 and IL-6.
PG  - 1645-54
LID - 10.1007/s00125-014-3249-1 [doi]
AB  - AIMS/HYPOTHESIS: Inflammation contributes to pancreatic beta cell dysfunction in 
      type 2 diabetes. Toll-like receptor (TLR)-2 and -4 ligands are increased 
      systemically in recently diagnosed type 2 diabetes patients, and TLR2- and 
      TLR4-deficient mice are protected from the metabolic consequences of a high-fat 
      diet. Here we investigated the role of macrophages in TLR2/6- and TLR4-mediated 
      effects on islet inflammation and beta cell function. METHODS: Genetic and 
      pharmacological approaches were used to determine the effects of TLR2/6 and TLR4 
      ligands on mouse islets, human islets and purified rat beta cells. Islet 
      macrophages were depleted and sorted by flow cytometry and the effects of TLR2/6- 
      and TLR4-activated bone-marrow-derived macrophages (BMDMs) on beta cell function 
      were assessed. RESULTS: Macrophages contributed to TLR2/6- and TLR4-induced islet 
      Il1a/IL1A and Il1b/IL1B mRNA expression in mouse and human islets and IL-1beta 
      secretion from human islets. TLR2/6 and TLR4 ligands also reduced insulin gene 
      expression; however, this occurred in a non-beta cell autonomous manner. TLR2/6- 
      and TLR4-activated BMDMs reduced beta cell insulin secretion partly via reducing 
      Ins1, Ins2, and Pdx1 mRNA expression. Antagonism of the IL-1 receptor and 
      neutralisation of IL-6 completely reversed the effects of activated macrophages 
      on beta cell gene expression. CONCLUSIONS/INTERPRETATION: We conclude that islet 
      macrophages are major contributors to islet IL-1beta secretion in response to TLR2/6 
      and TLR4 ligands. BMDMs stimulated with TLR2/6 and TLR4 ligands reduce insulin 
      secretion from pancreatic beta cells, partly via IL-1beta- and IL-6-mediated 
      decreased insulin gene expression.
FAU - Nackiewicz, Dominika
AU  - Nackiewicz D
AD  - Department of Surgery, Faculty of Medicine, The University of British Columbia, 
      Child and Family Research Institute, 950 W 28th Ave, Vancouver, BC, Canada, V5Z 
      4H4.
FAU - Dan, Meixia
AU  - Dan M
FAU - He, Wei
AU  - He W
FAU - Kim, Rosa
AU  - Kim R
FAU - Salmi, Anisa
AU  - Salmi A
FAU - Rutti, Sabine
AU  - Rutti S
FAU - Westwell-Roper, Clara
AU  - Westwell-Roper C
FAU - Cunningham, Amanda
AU  - Cunningham A
FAU - Speck, Madeleine
AU  - Speck M
FAU - Schuster-Klein, Carole
AU  - Schuster-Klein C
FAU - Guardiola, Beatrice
AU  - Guardiola B
FAU - Maedler, Kathrin
AU  - Maedler K
FAU - Ehses, Jan A
AU  - Ehses JA
LA  - eng
GR  - PCN-110793/Canadian Institutes of Health Research/Canada
GR  - PNI-120292/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140512
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (Insulin)
RN  - 0 (Interleukin-1)
RN  - 0 (Interleukin-6)
RN  - 0 (Toll-Like Receptors)
SB  - IM
MH  - Animals
MH  - Gene Expression Regulation
MH  - Humans
MH  - Insulin/*genetics/metabolism
MH  - Insulin-Secreting Cells/*metabolism
MH  - Interleukin-1/*metabolism
MH  - Interleukin-6/*metabolism
MH  - Islets of Langerhans/*metabolism
MH  - Macrophages/*metabolism
MH  - Mice, Knockout
MH  - Rats
MH  - Toll-Like Receptors/genetics/*metabolism
EDAT- 2014/05/13 06:00
MHDA- 2015/02/24 06:00
CRDT- 2014/05/13 06:00
PHST- 2013/10/28 00:00 [received]
PHST- 2014/04/08 00:00 [accepted]
PHST- 2014/05/13 06:00 [entrez]
PHST- 2014/05/13 06:00 [pubmed]
PHST- 2015/02/24 06:00 [medline]
AID - 10.1007/s00125-014-3249-1 [doi]
PST - ppublish
SO  - Diabetologia. 2014 Aug;57(8):1645-54. doi: 10.1007/s00125-014-3249-1. Epub 2014 
      May 12.