interleukin-1b (IL-1b)

see also:

• fever - the febrile response to infections
• interleukin-6 (IL-6)
• cytokines
• immunology

• an important mediator of the inflammatory response, and is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis.
• this and the eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2
• IL-1α and IL-1β are expressed in a wide range of tissues and a variety of cells, especially in macrophages in lymphoid organs including the thymus, spleen, lymph nodes, Peyer’s patches, and bone marrow as well as in tissue macrophages in the lung, digestive tract, and liver
• genetic and experimental data suggest that IL-1b and IL-6 (the upstream drivers of hepatic CRP production) do appear causally related to atherosclerotic disease

• pattern recognition receptors (PRRs) detect infection or noxious chemicals
  • one of these PRR types are the NOD-like receptors of which NLRP3 is of interest here
• in response to the NRLP3 binding a substance, it can interact with apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and caspase-1, and the resulting complex is a sensor of cell injury called “inflammasome” - an interleukin 1β processing platform that plays a crucial role in IL-1β maturation and secretion from cells.
• NRLP3 inflammasomes monitor membrane integrity and pore-forming toxins, crystals, and many other noxious stimuli
• Inflammasomes recognize danger signals and activate proinflamatory process and production of IL-1β and IL-18.
  • NLRP3 (contains three domain: pyrin domain, a nucleotide-binding domain and a leucine-rich-repeat) type of inflammasome is activated by various stimuli and there are documented several diseases connected to NLRP3 activation like type 2 diabetes mellitus , Alzheimer's disease, obesity and atherosclerosis
    • mutations in the inflammasome receptor NLRP3 cause Cryopyrin-Associated Periodic Syndromes (CAPS)
    • over-expression of IL-1β caused by inflammasome may result in carcinogenesis with links to colon cancer, melanoma and lung adenocarcinoma
    • NLRP3 inflammasomes have also been reported to be involved in low-grade subclinical inflammation induced by chronic exposure to high levels of free fatty acids and glucose, leading to increased apoptosis and impaired insulin secretion of β-cells in obese type 2 diabetes mellitus (T2D) patients
      • islet amyloid polypeptide (IAPP) oligomers activated NLRP3 inflammasomes to induce significant IL-1β production by infiltrating macrophages ¹⁾
      • Higher concentrations of glucose activate NF-κB and IL-1 precursors in cells
• IL-1β is produced in activated macrophages as a 269-AA precursor protein and processed by caspase-1, which is also known as IL-1β-converting enzyme (ICE), activated in inflammasomes, to the C-terminal 153 AA as mature IL-1β
• The IL-1β precursor is also processed by other serine proteases

• IL-1α and IL-1β are structurally similar and show the same functions by sharing a common receptor, IL-1 type 1 receptor (IL-1R1), and both have the same central β-barrel along with adjoining loops
• two receptors IL-1R1 and IL-1R2 (the latter is a decoy receptor which does not initiate signal transduction and is thought to reduce the biological response to IL-1)
• expression levels of IL-1R1 and IL-1R2 are different among the cell types
  • neutrophils predominantly express IL-1R2, thus much higher concentrations of IL-1β are required to activate neutrophils than for endothelial cells which express IL-1R1

• increases interleukin-6 (IL-6) production
• promotes the differentiation of monocytes into conventional dendritic cells (DCs) and M1-like macrophages
• supports the proliferation of activated B- lymphocytes and their differentiation into plasma cells
• high levels increase Th17-dominant immunopathology
• IL-1 in combination with IL-2 promoted not only the expansion of NK cells but also CD4+ CD8+ T-lymphocytes
• in combination with IL-23, induces expression of IL-17, IL-21 and IL-22 by γδT cells
  • this induction of expression is in the absence of additional signals and suggests IL-1β is involved in modulation of autoimmune inflammation
• IL-1β generated by activated antigen-presenting cells (APCs) induces type 1 immune responses, which produces cytotoxic T lymphocytes and led to the polarization of CD4+ T -lymphocytes towards T-helper cell type 1 (Th1)
• plays a role in resolving acute inflammation resulting in the initiation of adaptive anti-tumor responses
• induction of cyclooxygenase-2 (PTGS2/COX2) in the central nervous system (CNS) is found to contribute to inflammatory pain hypersensitivity

• Anakinra
  • a recombinant human intrinsic IL-1 receptor antagonist (IL-1Ra) developed in 1985
  • use in rheumatoid arthritis in 1993, then for many other conditions in the 2000's
• Canakinumab
  • a human IgGκ monoclonal antibody targeting IL-1β
  • significantly reduces hsCRP, IL-6, and fibrinogen without an apparent impact on LDLC or HDLC
  • reduces atherosclerosis dependent upon reduction in interleukin-6 (IL-6) levels in the 2017 CANTOS study of those who have PH AMI and a raised hsCRP, and reduces major recurrent adverse cardiovascular events or urgent coronary revascularization by 17% over a 3-4 yr study period and also reduced incident and fatal lung cancer by 75%! In addition, the study showed statistically significant and clinically relevant reductions in incident gout, anaemia, and large joint osteoarthritis,
  • is associated with a small increase of ≈1 per thousand in fatal infection, which were not opportunistic but were usual gram-positive infections typically in older individuals with concomitant diabetes.