Glioblastoma Multiforme (GBM) is a highly invasive and malignant primary brain. Despite aggressive treatment that currently includes surgical resection followed by radiation and chemotherapy, the recurrence of GBM is high with only 3-5% patients surviving longer than 3 years. GBM is refractory to treatment because it rapidly disseminates throughout the brain, develops a tumor microenvironment with GBM-initiated proinflammatory state characterized by the presence of cytokines, such as IL-1, which are secreted by both GBM cells and GBM-activated astrocytes. Our preliminary data show that IL-1 induces expression of transcription factor interferon regulatory factor 1 (IRF-1) in astrocytes. Newly synthesized IRF-1 is subsequently activated and induces the expression of potent chemokines CCL5 and CXCL10. The mechanism of IRF-1 activation remains elusive;however, other IRFs are activated by their K63-linked polyubiquitination and phosphorylation. Our preliminary data demonstrate that IL-1 induces K63-linked polyubiquitination of IRF-1 that is needed for its activation. Although, phosphorylation of IRF-1 has been reported, it is not clear whether it is also required for IRF-1 activation. IRF-1-dependent expression of CCL5 and CXCL10 in astrocytes likely affects GBM progression. Although both of these chemokines are commonly associated with monocyte and T lymphocyte chemotaxis, they both can increase GBM proliferation. Thus, our central hypothesis is that in response to IL-1, astrocytes upregulate expression of IRF-1-dependent chemokines CXCL10 and CCL5, which promote the proliferation, migration, and invasion of GBM cells in vivo. We propose the following aims to test this hypothesis:
Aim 1 : Determine whether phosphorylation of IRF-1 is a critical step in the activation of IRF-1 by IL-1.
Aim 2 : Evaluate the effect of astrocyte-derived CCL5 and CXCL10 on GBM proliferation, migration, and invasion in vitro.
Aim 3 : Determine the role of IRF-1 in both GBM development and progression in vivo. Completion of these aims will establish whether activation of IRF-1, CXCL10, and CCL5 contributes to GBM development and progression. It may also lead to new targets for the development of therapies in the future.
Glioblastoma Multiforme (GBM) is a highly invasive and malignant primary brain tumor that evades current aggressive treatments and initiates proinflammatory state in the brain characterized by the presence of cytokines, including IL-1. We found that IL-1 regulates expression of CCL5 and CXCL10 chemokines in astrocytes via the activation of interferon regulatory factor 1 (IRF-1) that includes its K63-linked polyubiquitinatio. Astrocyte-derived CCL5 and CXCL10 can promote the proliferation, migration, and invasion of GBM cells in vivo. Thus, understanding whether activation of IRF-1, CXCL10, and CCL5 in astrocytes contributes to GBM development and progression is critical, and may also lead to development of therapies in the future.
|Yester, Jessie W; Bryan, Lauren; Waters, Michael R et al. (2015) Sphingosine-1-phosphate inhibits IL-1-induced expression of C-C motif ligand 5 via c-Fos-dependent suppression of IFN-? amplification loop. FASEB J 29:4853-65|