IL-10 is pathogenic during the development of coxsackievirus B4-induced chronic pancreatitis

Abstract

Using a mouse model of coxsackievirus B4 (CVB4-V)-induced chronic pancreatitis; we investigated whether cytokines are involved in the progression of acute disease to chronic inflammatory disease. We show that IL-10 contributed to the development of chronic pancreatitis since acute disease resolved when IL-10 was absent or when IL-10 signaling was disrupted. We explored the underlying mechanisms by which IL-10 affected disease progression, using a novel approach to assess immunological events occurring in situ. Multiple markers that define functional innate immune responses and functional T cell responses were monitored over the course of CVB4-V infection of wild-type and IL-10 knockout mice, using a multiplex transcriptional profiling approach. We show that high levels of IL-10 early during infection were associated with delayed innate and T cell responses. Furthermore, high IL-10 production correlated with altered kinetics of T regulatory responses indicating a disruption in the balance between effector and regulatory T cell responses.

Dynamics of molecular responses to coxsackievirus B4 infection differentiate between resolution and progression of acute pancreatitis

“…The pancreas, harvested at various times after infection, was frozen immediately on dry ice and placed in 1 ml of lysis buffer containing protease inhibitors (50 mM Tris, 150n mM NaCl, 2 mM EDTA, 1% NP40, 30 µM PMSF, 420 µM leupeptin, 0.02% aprotinin, 3 mM NaN 3 ) (Gu et al, 2009). Organs were homogenized in a mini-beater (Biospec Products, Bartlesville, OK) using 1 mm Zirconia beads (Biospec Products).…”

“…Gene expression was quantified using the TaqMan Gene Expression Assay in a two-step RT-PCR and a TaqMan Low Density Array (LDA), a 384-well micro fluidic card, preloaded with appropriate PCR primers and probes (Applied Biosystems) (Gu et al, 2009). Total pancreatic RNA was reverse-transcribed with M-MLV RT and random hexamers in a reaction volume of 25 ul using standard conditions.…”

“…While the viral genotype determines the severity of acute pancreatitis, host factors govern the progression to chronic pancreatitis. We have recently shown that IL-10 plays a major role in the development of chronic pancreatitis (Gu et al, 2009). CVB4-V infection in IL-10 knockout (KO) mice or during disruption of IL-10 signaling in wild-type mice results in an acute pancreatitis that does not progress to chronic pancreatitis.…”

“…CVB4-V-induced acute pancreatitis was accompanied by increased expression of genes involved in apoptosis, acinoductular metaplasia, remodeling of the extracellular matrix, and fibrosis; consistent with the observed progression to chronic pancreatitis. We subsequently pursued a study to explore the temporal dynamics of molecular immune responses to CVB4-V infection during the early infectious phase of disease and showed that early high levels of IL-10 are associated with delayed innate and adaptive immune responses in BALB/c mice (Gu et al, 2009). The present study is an extension of this work and focuses on the temporal dynamics of molecular immune responses to CVB4-V infection at a later stage in the disease process, just prior to the development of chronic pancreatitis.…”

Risk Factors for Pancreatic Cancer: Underlying Mechanisms and Potential Targets

“…In contrast to its beneficial role in AP, IL-10 has been shown to be instrumental in the development of CP in an experimental animal model (Gu et al, 2009). Furthermore, cytokines TGF-β, TNF-α, IL-1, IL-6, and IL-10 have been shown to activate pancreatic stellate cells which could either result in tissue repair or the development of fibrosis [see section Pancreatic Stellate Cells (PSCs)] (Apte et al, 1999;Mews et al, 2002).…”