Inhibition of Pim-1 kinase ameliorates dextran sodium sulfate-induced colitis in mice.

Abstract

BACKGROUND:

Pim-1 kinase is involved in the control of cell growth, differentiation and apoptosis. Recent evidence suggests that Pim kinases play a role in immune regulation and inflammation. However, the role of Pim-1 kinase in inflammatory bowel diseases (IBD) remains unclear.

AIMS:

The aims of this study were to explore the role of Pim-1 kinase in the pathology of IBD and to assess whether inhibiting Pim-1 kinase may be of therapeutic benefit as a treatment regimen for IBD.

METHODS:

Colitic mouse model was established by the induction of dextran sodium sulfate. The expression of Pim-1 in the colonic samples of control and colitic mice was examined. Furthermore, the mice were treated with Pim-1inhibitor (PIM-Inh), then the body weight and colon inflammation were evaluated, and the production of cytokines including IFN-γ, IL-4, TGF-β and IL-17 in colon tissues was determined by ELISA. The expression of T cell master transcription factors T-bet, ROR-γt, GATA-3 and Foxp3 and Nuclear factor κB (NF-κB) and inducible nitric oxide synthase in colon tissues was detected by real-time PCR and western blot. Finally, the effect of LPS on Pim-1 expression and the effects of PIM-Inh on LPS-induced upregualtion of p65 and TNF-α in RAW264.7 cells were examined by real-time PCR and western blot.

RESULTS:

Pim-1 expression was correlated with the degree of mucosal inflammation in vivo, and it was significantly induced by LPS in vitro. PIM-Inh had protective effects on acute colitis in vivo. Mechanistically, PIM-Inh reduced the proinflammatory immune response through the inhibition of the overactivation of macrophages and the down-regulation of excessive Th1- and Th17-type immune responses. Furthermore, PIM-Inh could skew T cell differentiation towards a Treg phenotype.

CONCLUSIONS:

Pim-1 kinase is involved in mucosal injury/inflammation and Pim-1 kinase inhibitor may provide a novel therapeutic approach for IBD.

• Authors: Yue-Ming Shen, Yan Zhao, Ya Zeng, Lu Yan, Bo-Lin Chen, Ai-Min Leng, Yi-Bin Mu, Gui-Ying Zhang
• Journal: Digestive diseases and sciences (Dig Dis Sci) Vol. 57 Issue 7 Pg. 1822-31 (Jul 2012) ISSN: 1573-2568 [Electronic] United States
• PMID: 22466098 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Enzyme Inhibitors
• Lipopolysaccharides
• Transcription Factors
• Tumor Necrosis Factor-alpha
• Dextran Sulfate
• Proto-Oncogene Proteins c-pim-1
• eIF-2 Kinase

Topics

• Animals
• Cells, Cultured
• Colitis (chemically induced, metabolism, prevention & control)
• Colon (drug effects, metabolism, pathology)
• Cytokines (metabolism)
• Dextran Sulfate (adverse effects)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology, therapeutic use)
• In Vitro Techniques
• Lipopolysaccharides (pharmacology)
• Macrophages (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Proto-Oncogene Proteins c-pim-1 (antagonists & inhibitors, drug effects, metabolism)
• Transcription Factors (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation (drug effects)
• eIF-2 Kinase (metabolism)