Interleukin-1 beta(IL-1β) is the major driving force in neuroinflammation. Here, we report on (i) the role of (IL-1β) in activating a signaling cascade that leads to proliferation and metastasis in glioblastoma cancer pathogenesis as well as (ii) the therapeutic role for IL-1 Receptor Antagonist (IL-1RA) and Tolcapone against untoward aspects of tumor pathogenesis. Here, we report that IL-1β treatment at 50 ng/mL for 48 h increased proliferation and metastasis by 30-fold (p ≤ 0.05), leading to the formation of clones of rapidly dividing cancer cells, leading to the formation of organized glial fibrillary acid protein (GFAP)-immunoreactive, clone-like structures with protruding spikes. Further, IL-1β treatment significantly increased the expression of mRNA levels of the IL-1β-driven pathway TLR-MyD88-NF-κB-TNFα and IL-6 (p ≤ 0.05). IL-1β also increased autophagy via elevation of mRNA and protein levels of cathepsin B, LAMP-2, and LC3B. In contrast, IL-1RA and Tolcapone inhibited this proliferation and the expression of these mRNAs and proteins, inhibiting autophagy by downregulating these autophagy proteins and inducing apoptosis by upregulating the expression of pro-apoptotic proteins like caspase-8 and caspase-3. IL-1β and its receptor can be targeted for successful anticancer therapy, as shown here with the use of IL-1RA and/or Tolcapone.

Introduction: Here we consider the collision of a genetic factor and an essential instigator in Alzheimer’s neuropathogenesis: (i) the Alzheimer’s gene (APOEε4), which downregulates lysosomal autophagy and induces synthesis of (ii) the instigator, interleukin-1β (IL-1β), which drives synthesis of βAPP for Aβ plaques and of MAPKp38 for phosphorylation of tau for formation of neurofibrillary tangles (NFTs), the two cardinal features of AD. Methods: RT-PCR, immunoblotting and immunohistochemistry techniques were used to assess the levels of IL-1β and its signaling cascade in ADε4,4, ε3,3, and age-matched controls (AMC3,3) in hippocampal regions of the brain. Results: IL-1β and its downstream signaling proteins TLR-2, MyD88, NFκB, COX-1, and COX-2 were greater in tissues from ADε4,4 than ADε3,3 or AMC3,3. Cathepsin B, D, and L levels, which play a pivotal role and are necessary for lysosomal autophagy, were lower in ADε4,4 than in ADε3,3 or AMC ε3,3. IL-1β and its downstream signaling cascade TLR-2, MyD88, NFκB, COX-1, and COX-2 expression levels were high in SH-SY5Y and T98G cells transfected with APOεE4. Conclusions: APOEε4 causes Alzheimer’s by downregulating autophagy, thus inducing IL-1β for Aβ plaque and neurofibrillary tangle formation.

Neuroinflammation, read as elevated levels of Interleukin-1β (IL-1β) and of its downstream signaling cascade, has been shown to play a neuropathogenic role in numerous neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. Western blotting was used to determine the effects of IL-1β and its signaling cascade on Human Oligodendroglioma (HOG) and Schwann cells and to evaluate the potential therapeutic effects of Ibuprofen and Flurbiprofen on MS pathogenesis in vitro. IL-1β increased neuroinflammatory markers like TNFα, MyD88, βAPP, COX-2, and IL-6, as well as transcription factors like NFκB and STAT in HOG and Schwann cells, which in turn regulate the expression of other cytokines, resulting in the activation of the self-perpetuating Cytokine Cycle. The IL-1β treatment of HOG and Schwann cells decreased the levels of myelin Basic Protein (MBP) and synaptophysin while at the same time increasing βAPP. Autophagy markers like LAMP-2 and LC3B were downregulated. In contrast, treatment with Ibuprofen and Flurbiprofen effectively countered the harmful effects of IL-1β in MS. These in vitro studies show that IL-1β can play a possible detrimental role in facilitating neuropathogenesis, as seen in Alzheimer’s and Parkinson’s disease, and anti-inflammatory drugs Ibuprofen and Flurbiprofen have a potential role in modulating the neuroinflammation in MS.