Enhanced susceptibility to lipopolysaccharide-induced arthritis and endotoxin shock in interleukin-32 alpha transgenic mice through induction of tumor necrosis factor alpha Reportar como inadecuado

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Arthritis Research and Therapy

, 14:R120

First Online: 21 May 2012Received: 19 December 2011Revised: 01 May 2012Accepted: 21 May 2012


IntroductionThe present study assessed the potential functions of interleukin IL-32α on inflammatory arthritis and endotoxin shock models using IL-32α transgenic Tg mice. The potential signaling pathway for the IL-32-tumor necrosis factor TNFα axis was analyzed in vitro.

MethodsIL-32α Tg mice were generated under control of a ubiquitous promoter. Two disease models were used to examine in vivo effects of overexpressed IL-32α: Toll-like receptor TLR ligand-induced arthritis developed using a single injection of lipopolysaccharide LPS or zymosan into the knee joints; and endotoxin shock induced with intraperitoneal injection of LPS and D-galactosamine. TNFα antagonist etanercept was administered simultaneously with LPS in some mice. Using RAW264.7 cells, in vitro effects of exogenous IL-32α on TNFα, IL-6 or macrophage inflammatory protein 2 MIP-2 production were assessed with or without inhibitors for nuclear factor kappa B NFκB or mitogen-activated protein kinase MAPK.

ResultsSingle injection of LPS, but not zymosan, resulted in development of severe synovitis with substantial articular cartilage degradation in knees of the Tg mice. The expression of TNFα mRNA in inflamed synovia was highly upregulated in the LPS-injected Tg mice. Moreover, the Tg mice were more susceptive to endotoxin-induced lethality than the wild-type control mice 48 hours after LPS challenge; but blockade of TNFα by etanercept protected from endotoxin lethality. In cultured bone marrow cells derived from the Tg mice, overexpressed IL-32α accelerated production of TNFα upon stimulation with LPS. Of note, exogenously added IL-32α alone stimulated RAW264.7 cells to express TNFα, IL-6, and MIP-2 mRNAs. Particularly, IL-32α -induced TNFα, but not IL-6 or MIP-2, was inhibited by dehydroxymethylepoxyquinomicin DHMEQ and U0126, which are specific inhibitors of nuclear factor kappa B NFκB and extracellular signal regulated kinase1-2 ERK1-2, respectively.

ConclusionsThese results show that IL-32α contributed to the development of inflammatory arthritis and endotoxin lethality. Stimulation of TLR signaling with LPS appeared indispensable for activating the IL-32α-TNFα axis in vivo. However, IL-32α alone induced TNFα production in RAW264.7 cells through phosphorylation of inhibitor kappa B IκB and ERK1-2 MAPK. Further studies on the potential involvement of IL-32α-TNFα axis will be beneficial in better understanding the pathology of autoimmune-related arthritis and infectious immunity.

AbbreviationsBMbone marrow


DMSOdimethyl sulfoxide

DSSdextran sodium sulfate

ELISAenzyme-linked immunosorbent assay

ERK1-2extracellular signal regulated kinase1-2

FCSfetal calf serum

IκBinhibitor kappa B



MAPKmitogen-activated protein kinase

MIPmacrophage inflammatory protein

MyD88myeloid differentiation factor 88

NF-κBnuclear factor kappa B

NKnatural killer

NODnucleotide-binding oligomerization domain-containing protein

PBMCperipheral blood mononuclear cell

PBSphosphate-buffered saline

PCRpolymerase chain reaction

RArheumatoid arthritis

rIL-32αrecombinant human interleukin-32α protein


TLRToll-like receptor

TNFtumor necrosis factor

Wtwild-type C57BL-6 Jcl.

Electronic supplementary materialThe online version of this article doi:10.1186-ar3850 contains supplementary material, which is available to authorized users.

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Autor: Masanori Nakayama - Yasuo Niki - Toshiki Kawasaki - Yuki Takeda - Keisuke Horiuchi - Aya Sasaki - Yasunori Okada - Kazuo U

Fuente: https://link.springer.com/

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