Critical role for apoptosis signal-regulating kinase 1 in the development of inflammatory K/BxN serum-induced arthritis.
In this report, we show that apoptosis signal-regulating kinase 1(-/-) (ASK1 KO) mice were resistant to inflammatory arthritis induced in the K/BxN serum transfer model of rheumatoid arthritis (RA). The p38 inhibitor, SD-0006 was administered to wild type (WT) mice as a comparator. Both ASK1 KO and p38 inhibition resulted in marked attenuation of edema, cartilage damage, bone resorption, and general inflammatory responses. Transcriptional profiling of mRNA prepared from paw tissue demonstrated that the production of many proinflammatory genes including cytokines, chemokines, and extracellular matrix degradative enzymes were maintained at basal levels by either ASK1 KO or prophylactic p38 MAPK inhibition. In the mouse whole blood (MWB) assay, tumor necrosis factor-α (TNF-α)-induced KC and CCL2 levels and also LPS-induced interleukin-6 (IL-6), CCL2, and KC levels in MWB from ASK1 KO were significantly lower than those from WT. Furthermore, both p38 and JNK were activated by TNF-α in human synovial fibroblasts isolated from RA patients (RASF). SD-0006 or SP600125, a JNK inhibitor, partially blocked the elevation of IL-6 production in RASF following stimulation with TNF-α. In contrast, dual inhibition with both p38/JNK inhibitors almost completely abolished TNF-α-induced IL-6 production from these cells. Ablation of ASK1 expression in RASF using siRNA for ASK1 resulted in inhibition of TNF-α-induced IL-6 and PGE(2) production. This study is the first to suggest that ASK1 is critical for the development of RA and that ASK1 may be involved in the production of proinflammatory mediators in response to TNF-α stimulation in the RA joint.
Mnich
Stephen J
SJ
Discovery Biology, Global Research and Development, St. Louis Laboratories Pfizer Inc., 700 Chesterfield Parkway West, mail zone AA3C, Chesterfield, MO 63017, USA.
Blanner
Patrick M
PM
Hu
Liangbiao G
LG
Shaffer
Alexander F
AF
Happa
Fernando A
FA
O'Neil
Shawn
S
Ukairo
Okechukwu
O
Weiss
Dave
D
Welsh
Eric
E
Storer
Chad
C
Mbalaviele
Gabriel
G
Ichijo
Hidenori
H
Monahan
Joseph B
JB
Hardy
Medora M
MM
Eda
Hiroyuki
H
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001168:Arthritis / Q000139:chemically induced* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D002478:Cells, Cultured; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D015850:Interleukin-6; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011720:Pyrazoles / Q000633:toxicity; D011743:Pyrimidines / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015850:Interleukin-6; D011720:Pyrazoles; D011743:Pyrimidines; C545840:SD 0006; D014409:Tumor Necrosis Factor-alpha; D048848:MAP Kinase Kinase Kinase 5; D015232:Dinoprostone