Interleukin-1 (IL-1) Pathway

Abstract

The interleukin-1 (IL-1) family of cytokines comprises 11 proteins (IL-1F1 to IL-1F11) encoded by 11 distinct genes in humans and mice. IL-1-type cytokines are major mediators of innate immune reactions, and blockade of the founding members IL-1alpha or IL-1beta by the interleukin-1 receptor antagonist (IL-1RA) has demonstrated a central role of IL-1 in a number of human autoinflammatory diseases. IL-1alpha or IL-1beta rapidly increase messenger RNA expression of hundreds of genes in multiple different cell types. The potent proinflammatory activities of IL-1alpha and IL-1beta are restricted at three major levels: (i) synthesis and release, (ii) membrane receptors, and (iii) intracellular signal transduction. This pathway summarizes extracellular and intracellular signaling of IL-1alpha or IL-1beta, including positive- and negative-feedback mechanisms that amplify or terminate the IL-1 response. In response to ligand binding of the receptor, a complex sequence of combinatorial phosphorylation and ubiquitination events results in activation of nuclear factor kappaB signaling and the JNK and p38 mitogen-activated protein kinase pathways, which, cooperatively, induce the expression of canonical IL-1 target genes (such as IL-6, IL-8, MCP-1, COX-2, IkappaBalpha, IL-1alpha, IL-1beta, MKP-1) by transcriptional and posttranscriptional mechanisms. Of note, most intracellular components that participate in the cellular response to IL-1 also mediate responses to other cytokines (IL-18 and IL-33), Toll-like-receptors (TLRs), and many forms of cytotoxic stresses.

Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis

“…While some of those, namely the mitogen-activated protein kinase kinase 4 (MKK4 or MEK4), can activate both JNK and p38, others specifically activate each of these MAPK. MKK3 and MKK6 are p38 activators while MKK7 activates JNK and MKK1 activates ERK1/2 (Weber et al, 2010). Thus, limonene may inhibit MKK3 or MKK6 without affecting MKK4 or MKK7 or any other upstream intermediate, while inducing MKK1 activation, either direct or indirectly.…”

Interleukin-1β activates focal adhesion kinase and Src to induce matrix metalloproteinase-9 production and invasion of MCF-7 breast cancer cells

“…These results identify IL-1β as one of the essential components mediating inflammation-associated tumor progression. IL-1β stimulation of tumor cells activates multiple signaling pathways involving protein kinase B, mitogen activated protein (MAP) kinase, and nuclear factor-κB (12). Activation of these signaling molecules is required for IL-1β-mediated production of matrix metalloproteinase (MMP)-9, a matrix degrading enzyme that is regarded as a critical regulator in IL-1β-induced tumor invasion (13)(14)(15).…”

Vaccination with human induced pluripotent stem cells creates an antigen-specific immune response against HIV-1 gp160

“…Cytokine production from irradiated hiPSCs might promote the activation of APCs thereby enhancing cellular immunity against loaded antigen. IL-1α has been shown to be a potent pro-inflammatory cytokine and directly up-regulate NF-κB signaling resulting in the activation of dendritic cells and macrophages (Ardeshna et al, 2000; Yoshimura et al, 2003; Weber et al, 2010). Although much progress has been made in dissecting the complexity of the cytokine network, the role of cytokines from pluripotent stem cells has not been well characterized.…”