Previous content was shared[Cytokines].The content focuses on the types of cytokines and their clinical applications. Through the sharing of these dry knowledge, I hope that all the experimenters can gain something and help you solve the difficult problems encountered before the experiment is carried out (attached at the end of the article.)[Cytokines].Related content).
We'll continue to share it with youNew Theme Series – Target Interpretation。Focus on the analysis of disease-related hot indicators, and promote the research on the pathogenesis and prevention and treatment of diseases. In this issue, we will take a comprehensive lookPro-inflammatory cytokine – IL-1
Introduction to IL-1
Interleukin-1 (IL-1) is also known as leukocyte pyrogen, endogenous mediator of leukocytes, monocyte cytokines, lymphocyte activating factor, etc., and human IL-1 is a cytokine protein encoded by the IL-1 gene.
IL-1 was first cloned in the 1980s and was soon recognized as a key factor in regulating the inflammatory process. IL-1 is a canonical pro-inflammatory cytokine that is essential for a defensive response to host infection and injury. It is expressed in various tissues and cells, especially in macrophages of lymphoid organs, including thymus, spleen, lymph nodes and bone marrow, and also in tissue macrophages of non-lymphoid organs such as lungs, digestive tract, liver, etc.
IL-1**
IL-1 can exert effects in a variety of ways, such as autocrine, paracrine, and endocrine, so IL-1 can act on the cells that produce it or neighboring cells to act locally, or it can act on distant target cells through endocrine means to mediate systemic reactions. However, it is stored in a precursor state and is highly degradable, and the cells in question will initiate IL-1 gene transcription immediately after stimulation by inflammatory factors, which is short and the transcript products are highly degraded [1].
Figure 1Schematic diagram of the synthesis of IL-1[2].
IL-1 is a biologically inactive precursor peptide. IL-1 precursors (pro-IL-1) and NLRP3 are transcribed, translated, and synthesized when there is a pro-inflammatory signal that activates the pattern recognition receptor (PRR), or when IL-1 and IL-1 bind to the IL-1 receptor (IL-1R) to form a positive feedback loop. NLRP3 is then activated by cholesterol crystals phagocytosed by macrophages, OX-LDL, or potassium efflux. Activated NLRP3 then recruits the adaptor protein ASC to link NLRP3 to precaspase-1, facilitating the hydrolysis of the latter into active caspase-1. Finally, pro-IL-1 is hydrolyzed by caspase-1 to mature and active IL-1 (molecular weight approximately 17 kDa).
Due to the wide range of functions of IL-1, its biological activity is tightly regulated. IL-1 signaling is negatively regulated by the deception receptor IL1-RII and the receptor antagonist IL1RA. There are three main levels of control to limit the potential pro-inflammatory activity of IL-1:
control the synthesis and release of NALp3-inflammasome, and the activation of IL-1 processing protease caspase-1;
control of membrane receptors;
Regulates signal transduction downstream of activated receptors.
IL-1 signaling pathway
Figure 2IL-1 signaling[4].
IL-1 signaling is primarily mediated by the IL-1 receptor-associated kinase pathway (IPAK pathway). First, after IL-1 binds to IL-1R, IL-1, IL-1R type I (IL-1R1) and IL-1R accessory protein (IL-1RACP) form heterotrimers. Protein kinase 4 (IPAk4) and bone marrow differentiation factor-88 (MYD88) were activated, while IL-1R-activated protein kinase 4 autophosphorylated, IPAK1 and IPAK2 were phosphorylated, followed by recruitment of oligomerization tumor necrosis factor receptor-related factor (TRAF6), and activated TRAF6 activated the MAPKKK family of mitogen-binding protein kinases. Intranuclear transcription factors then induce the activation of kinases (NIKs), and the unrepressed nuclear transcription factors (NF-B) are transferred to the nucleus to regulate the expression of related genes[3].
After the IL-1 signaling pathway is activated, it also affects other signaling pathways, such as NF-B, MAPKS, activator protein-1 (AP-1), JNK, p38 MAPK, etc., and further induces the expression of related genes, such as IL-6, IL-8, MCP-1, COX-2, IL-1, IL-1, etc[4].
Clinical use of IL-1
Associated diseases
IL-1 and intervertebral disc degeneration (IDD).
Low back pain (LBP) is a highly prevalent chronic condition that is expensive but not complete. Among the many possible causes of LBP, IDD is the most common, while IL-1-exacerbated inflammatory processes are considered a key event during IDD. Data suggest that patients with chronic low back pain with lumbar disc herniation have significantly upregulated IL-1 levels [5,6], modulated the production of disc chemokines [7], and induced the production of IL-6, IL-8, and IL-17 [8,9].
IL-1 and atherosclerosis (AS).
IL-1 plays a role in all stages of atherosclerosis. In the initial stage of the disease, it promotes the accumulation of inflammatory cells in the blood vessels and their invasion of the local intima of the blood vessels; In the acute phase of the disease, the reactants in the acute phase are increased, resulting in the formation of atherosclerotic thrombosis [10,11].
IL-1 and Alzheimer's disease (AD).
Microglia are closely associated with amyloid (A) plaques in postmortem tissues and animal models of AD patients; Recognition and phagocytosis of soluble A-peptides can trigger microglial activation in vitro and in vivo and lead to the subsequent release of pro-inflammatory cytokines and chemokines, including IL-1. Elevated IL-1 levels have been reported in cerebrospinal fluid and brain tissue of patients in AD and AD mouse models [12].
IL-1 and tumors
IL-1 is involved in the occurrence and development of tumors, and overexpression of IL-1 may lead to tumorigenesis and promote tumor invasion. There is evidence that IL-1 is upregulated in many solid tumors, including melanoma, colon, lung, breast, and head and neck cancers, making it an excellent tumor biomarker and immunomodulator in cancer** [13]. IL-1 has been widely demonstrated to be upregulated in the development of ovarian, lung, and gastrointestinal cancers, which are generally associated with poor prognosis. Studies have shown that key polymorphisms in IL-1+3954 are risk factors for cachexia in patients with gastrointestinal cancers [14].
Latest patent for blocking IL-1
There are currently four strategies to block excess IL-1:
IL-1RA (IL-1 receptor antagonist preparation Anakina);
IL-1 receptor antagonists-IL-1 chimeras;
Monoclonal antibodies that neutralize IL-1;
Soluble IL-1 decoy receptors.
Obviously, making antibodies that neutralize IL-1 is a straightforward approach. Recently, several new patents have been issued for the production of humanized anti-IL-1 antibodies (Figure 3).
Figure 3Recent patents and applications for blocking IL-1 molecules[15]References:
dianrello ca,donath my ,maudrup-poulsen t,role of il-1beta in type 2 diabetes[j].curr opin endocrinol diabetes obes,2010,17(4):314-321.
wang y, che m, xin j, zheng z, li j, zhang s. the role of il-1β and tnf-α in intervertebral disc degeneration. biomed pharmacother. 2020 nov;131:110660.
gabay c,lamacchia c,palmer g.il-1 pathways in inflammation and humandiseases[j].nat rev rheumatol 2010(06):232-41.
mai w, liao y. targeting il-1β in the treatment of atherosclerosis. front immunol. 2020 dec 10;11:589654.
p. andrade, g. hoogland, m.a. garcia, h.w. steinbusch, m.a. daemen, v. visser-vandewalle, elevated il-1β and il-6 levels in lumbar herniated discs in patients with sciatic pain, eur. spine j. 22 (4) (2013) 714–720.
s. ohtori, g. inoue, y. eguchi, s. orita, m. takaso, n. ochiai, s. kishida,k. kuniyoshi, y. aoki, j. nakamura, t. ishikawa, g. arai, m. miyagi, h. kamoda, m. suzuki, y.sakuma, y. oikawa, g. kubota, k. inage, t. sainoh, t. toyone, k. yamauchi, t. kotani, t. akazawa, s. minami, k. takahashi, tumor necrosis factor- αimmunoreactive cells in nucleus pulposus in adolescent patients with lumbar disc herniation, spine 38 (6) (2013) 459–462.
k.l. phillips, k. cullen, n. chiverton, a.l. michael, a.a. cole, l.m. breakwell, g. haddock, r.a. bunning, a.k. cross, c.l. le maitre, potential roles of cytokines and chemokines in human intervertebral disc degeneration: interleukin-1 is a master regulator of catabolic processes, osteoarthr. cartil. 23 (7) (2015) 1165–1177.
g.q. teixeira, c.l. pereira, j.r. ferreira, a.f. maia, m. gomez-lazaro, m. a. barbosa, c. neidlinger-wilke, r.m. goncalves, immunomodulation of human mesenchymal stem/stromal cells in intervertebral disc degeneration: insights from a proinflammatory/degenerative ex vivo model, spine 43 (12) (2018) e673–e682.
h.e. gruber, g.l. hoelscher, j.a. ingram, h.j. norton, e.n. hanley, increased il-17 expression in degenerated human discs and increased production in cultured annulus cells exposed to il-1ß and tnf- αbiotech. histochem. 88 (6) (2013) 302–310.
bevilacqua mp, pober js, wheeler me, cotran rs, gimbrone ma jr. interleukin-1 activation of vascular endothelium. effects on procoagulant activity and leukocyte adhesion. am j pathol. 1985 dec;121(3):394-403.
beltrami-moreira m, vromman a, sukhova gk, folco ej, libby p. redundancy of il-1 isoform signaling and its implications for arterial remodeling. plos one. 2016 mar 31;11(3):e0152474.
babcock aa, ilkjær l, clausen bh, villadsen b, dissing-olesen l, bendixen at, lyck l, lambertsen kl, finsen b. cytokine-producing microglia h**e an altered beta-amyloid load in aged app/ps1 tg mice. brain beh** immun. 2015 aug;48:86-101.
batra r, suh mk, carson js, dale ma, meisinger tm, fitzgerald m, opperman pj, luo j, pipinos ii, xiong w, baxter bt. il-1β (interleukin-1β) and tnf-α tumor necrosis factor-α)impact abdominal aortic aneurysm formation by differential effects on macrophage polarization. arterioscler thromb vasc biol. 2018 feb;38(2):457-463.
zhang d, zheng h, zhou y, tang x, yu b, li j. association of il-1beta gene polymorphism with cachexia from locally advanced gastric cancer. bmc cancer. 2007 mar 14;7:45.
zhang h. anti-il-1β therapies. recent pat dna gene seq. 2011 aug;5(2):126-35.
Read more about cytokines
elabscience cytokines how much do you know about cytokineselabscience cytokines丨how much do you know about chemokineselabscience cytokines** points.