TY  - JOUR
A1  - Krupkova, Olga
A1  - Sadowska, Aleksandra
A1  - Kameda, Takuya
A1  - Hitzl, Wolfgang
A1  - Hausmann, Oliver Nic
A1  - Klasen, Jürgen
A1  - Wuertz-Kozak, Karin
T1  - p38 MaPK Facilitates crosstalk Between endoplasmic reticulum stress and IL-6 release in the intervertebral Disc
JF  - Frontiers in Immunology
N2  - Degenerative disc disease is associated with increased expression of pro-inflammatory cytokines in the intervertebral disc (IVD). However, it is not completely clear how inflammation arises in the IVD and which cellular compartments are involved in this process. Recently, the endoplasmic reticulum (ER) has emerged as a possible modulator of inflammation in age-related disorders. In addition, ER stress has been associated with the microenvironment of degenerated IVDs. Therefore, the aim of this study was to analyze the effects of ER stress on inflammatory responses in degenerated human IVDs and associated molecular mechanisms. Gene expression of ER stress marker GRP78 and pro-inflammatory cytokines IL-6, IL-8, IL-1 beta, and TNF-alpha was analyzed in human surgical IVD samples (n = 51, Pfirrmann grade 2-5). The expression of GRP78 positively correlated with the degeneration grade in lumbar IVDs and IL-6, but not with IL-1 beta and TNF-alpha. Another set of human surgical IVD samples (n = 25) was used to prepare primary cell cultures. ER stress inducer thapsigargin (Tg, 100 and 500 nM) activated gene and protein expression of IL-6 and induced phosphorylation of p38 MAPK. Both inhibition of p38 MAPK by SB203580 (10 mu M) and knockdown of ER stress effector CCAAT-enhancer-binding protein homologous protein (CHOP) reduced gene and protein expression of IL-6 in Tg-treated cells. Furthermore, the effects of an inflammatory microenvironment on ER stress were tested. TNF-alpha (5 and 10 ng/mL) did not activate ER stress, while IL-1 beta (5 and 10 ng/mL) activated gene and protein expression of GRP78, but did not influence [Ca2+](i) flux and expression of CHOP, indicating that pro-inflammatory cytokines alone may not induce ER stress in vivo. This study showed that IL-6 release in the IVD can be initiated following ER stress and that ER stress mediates IL-6 release through p38 MAPK and CHOP. Therapeutic targeting of ER stress response may reduce the consequences of the harsh microenvironment in degenerated IVD.
KW  - intervertebral disc
KW  - inflammation
KW  - endoplasmic reticulum stress
KW  - p38 MAPK
KW  - CHOP
KW  - GADD153
KW  - GRP78
KW  - IL-6
Y1  - 2018
U6  - https://doi.org/10.3389/fimmu.2018.01706
SN  - 1664-3224
VL  - 9
PB  - Frontiers Research Foundation
CY  - Lausanne
ER  - 
TY  - GEN
A1  - Krupkova, Olga
A1  - Sadowska, Aleksandra
A1  - Kameda, Takuya
A1  - Hitzl, Wolfgang
A1  - Hausmann, Oliver Nic
A1  - Klasen, Jürgen
A1  - Wuertz-Kozak, Karin
T1  - p38 MaPK facilitates crosstalk between endoplasmic reticulum stress and IL-6 release in the intervertebral Disc
T2  - Postprints der Universität Potsdam : Humanwissenschaftliche Reihe
N2  - Degenerative disc disease is associated with increased expression of pro-inflammatory cytokines in the intervertebral disc (IVD). However, it is not completely clear how inflammation arises in the IVD and which cellular compartments are involved in this process. Recently, the endoplasmic reticulum (ER) has emerged as a possible modulator of inflammation in age-related disorders. In addition, ER stress has been associated with the microenvironment of degenerated IVDs. Therefore, the aim of this study was to analyze the effects of ER stress on inflammatory responses in degenerated human IVDs and associated molecular mechanisms. Gene expression of ER stress marker GRP78 and pro-inflammatory cytokines IL-6, IL-8, IL-1 beta, and TNF-alpha was analyzed in human surgical IVD samples (n = 51, Pfirrmann grade 2-5). The expression of GRP78 positively correlated with the degeneration grade in lumbar IVDs and IL-6, but not with IL-1 beta and TNF-alpha. Another set of human surgical IVD samples (n = 25) was used to prepare primary cell cultures. ER stress inducer thapsigargin (Tg, 100 and 500 nM) activated gene and protein expression of IL-6 and induced phosphorylation of p38 MAPK. Both inhibition of p38 MAPK by SB203580 (10 mu M) and knockdown of ER stress effector CCAAT-enhancer-binding protein homologous protein (CHOP) reduced gene and protein expression of IL-6 in Tg-treated cells. Furthermore, the effects of an inflammatory microenvironment on ER stress were tested. TNF-alpha (5 and 10 ng/mL) did not activate ER stress, while IL-1 beta (5 and 10 ng/mL) activated gene and protein expression of GRP78, but did not influence [Ca2+](i) flux and expression of CHOP, indicating that pro-inflammatory cytokines alone may not induce ER stress in vivo. This study showed that IL-6 release in the IVD can be initiated following ER stress and that ER stress mediates IL-6 release through p38 MAPK and CHOP. Therapeutic targeting of ER stress response may reduce the consequences of the harsh microenvironment in degenerated IVD.
T3  - Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe - 705 
KW  - intervertebral disc
KW  - inflammation
KW  - endoplasmic reticulum stress
KW  - p38 MAPK
KW  - CHOP
KW  - GADD153
KW  - GRP78
KW  - IL-6
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-468698
SN  - 1866-8364
IS  - 705
ER  -