Role of Integrin-linked kinase in innate immunity and in inflammatory diseases. — ASN Events
  1. Schedule
  2. Poster Session 1
  3. Role of Integrin-linked kinase in innate immunity and in inflammatory diseases.

Role of Integrin-linked kinase in innate immunity and in inflammatory diseases. (#3)

Afsar U. Ahmed 1 , Gregory E. Hannigan 1 , Bryan R. G. Williams 1
  1. MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia

Aims:

1.      To determine ILK-mediated signaling events in the innate immune system.

2.      To investigate the effect of myeloid cell-specific in vivo knockdown of ILK in mouse models of ulcerative colitis and colon cancer.

Methods:

In order to understand the role of ILK in immunity, we utilized (1) a small molecule inhibitor of ILK, (2) ex vivo knockdown of ILK in ILK fl/fl MEFS using AdenoCre virus and (3) in vivo myeloid cell-specific knockdown of ILK (ILK fl/fl;LysMCre).

Results:

Pharmacologic or genetic inhibition of ILK in mouse embryonic fibroblasts (MEFs) and macrophages selectively blocks LPS-induced production of the pro-inflammatory cytokine tumor necrosis factor α (TNF-α). ILK is required for LPS-induced activation of nuclear factor kB (NF-kB) and transcriptional induction of TNF-α. The modulation of LPS-induced TNF-α synthesis by ILK does not involve the classical NF-kB pathway, since IkB-α degradation and p65 nuclear translocation are both unaffected by ILK inhibition. Instead, ILK is involved in an alternative activation of NF-kB signaling by modulating the phosphorylation of p65 at Ser536. Furthermore, ILK-mediated alternative NF-kB activation through p65 Ser536 phosphorylation also occurs during Helicobacter pylori infection in macrophages and gastric cancer cells. Moreover, ILK is required for H. pylori-induced TNF-α secretion in macrophages. While ILK-mediated phosphorylation of p65 at Ser536 is independent of the phosphotidylinositol 3-kinase (PI3K)/Akt pathway during LPS stimulation, upon H. pylori infection this event is dependent on the PI3K/Akt pathway. Moreover, in mouse model of DSS-induced colitis, DSS-induced colon tissue damages, macrophages infiltration and colitis disease activity (measured by colon length, body weight loss and disease activity index) were significantly reduced in ILKfl/fl;LysMCre mice compared to the control mice, indicating a critical role of ILK in inflammatory diseases.

Conclusions:

Our findings implicate ILK as a critical regulatory molecule for pro-inflammatory signaling and a potential target for therapeutic intervention in inflammatory diseases.