| First Author | Nakayama M | Year | 2012 |
| Journal | Arthritis Res Ther | Volume | 14 |
| Issue | 3 | Pages | R120 |
| PubMed ID | 22613074 | Mgi Jnum | J:321143 |
| Mgi Id | MGI:6858284 | Doi | 10.1186/ar3850 |
| Citation | Nakayama M, et al. (2012) Enhanced susceptibility to lipopolysaccharide-induced arthritis and endotoxin shock in interleukin-32 alpha transgenic mice through induction of tumor necrosis factor alpha. Arthritis Res Ther 14(3):R120 |
| abstractText | INTRODUCTION: The present study assessed the potential functions of interleukin (IL)-32alpha on inflammatory arthritis and endotoxin shock models using IL-32alpha transgenic (Tg) mice. The potential signaling pathway for the IL-32-tumor necrosis factor (TNF)alpha axis was analyzed in vitro. METHODS: IL-32alpha Tg mice were generated under control of a ubiquitous promoter. Two disease models were used to examine in vivo effects of overexpressed IL-32alpha: 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. TNFalpha antagonist etanercept was administered simultaneously with LPS in some mice. Using RAW264.7 cells, in vitro effects of exogenous IL-32alpha on TNFalpha, IL-6 or macrophage inflammatory protein 2 (MIP-2) production were assessed with or without inhibitors for nuclear factor kappa B (NFkappaB) or mitogen-activated protein kinase (MAPK). RESULTS: Single 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 TNFalpha 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 TNFalpha by etanercept protected from endotoxin lethality. In cultured bone marrow cells derived from the Tg mice, overexpressed IL-32alpha accelerated production of TNFalpha upon stimulation with LPS. Of note, exogenously added IL-32alpha alone stimulated RAW264.7 cells to express TNFalpha, IL-6, and MIP-2 mRNAs. Particularly, IL-32alpha -induced TNFalpha, but not IL-6 or MIP-2, was inhibited by dehydroxymethylepoxyquinomicin (DHMEQ) and U0126, which are specific inhibitors of nuclear factor kappa B (NFkappaB) and extracellular signal regulated kinase1/2 (ERK1/2), respectively. CONCLUSIONS: These results show that IL-32alpha contributed to the development of inflammatory arthritis and endotoxin lethality. Stimulation of TLR signaling with LPS appeared indispensable for activating the IL-32alpha-TNFalpha axis in vivo. However, IL-32alpha alone induced TNFalpha production in RAW264.7 cells through phosphorylation of inhibitor kappa B (IkappaB) and ERK1/2 MAPK. Further studies on the potential involvement of IL-32alpha-TNFalpha axis will be beneficial in better understanding the pathology of autoimmune-related arthritis and infectious immunity. |
