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Treating the Underlying Causes of Synovitis, Degenerative Joint Disease and Osteoarthritis in Primary Care
Published in Kohlstadt Ingrid, Cintron Kenneth, Metabolic Therapies in Orthopedics, Second Edition, 2018
Interestingly, cells express a decoy-type, non-signaling IL-1R2 which helps to scavenge excess IL-1. As well, cells that are activated by IL-1 produce and release small amounts of the IL-1 inhibitor – IL-1Ra (receptor antagonist) – which has a downregulating effect on the IL-1 inflammatory cascade [37]. It is understood that high levels of IL-1Ra are needed to effectively balance the impact of IL-1 [38]. There is growing evidence that the introduction of IL-1Ra into joints results in significant downregulation of the inflammatory cascade [39].
Molecular diagnosis of endometrial receptivity
Published in Carlos Simón, Linda C. Giudice, The Endometrial Factor, 2017
Jose Miravet-Valenciano, Nuria Balaguer, Felipe Vilella, Carlos Simón
Finally, the IL-1 family includes agonists (IL-1α and IL-1β), cell surface receptors (IL-1R1 and IL-1R2), an accessory protein (IL-1RAcP), and an antagonist, IL-1ra (80–82). They are expressed throughout the menstrual cycle in both stromal and epithelial cells. IL-1β is detected at higher levels in stromal cells, macrophages, leukocytes, and endothelial cells during the late secretory phase (70). Further, this cytokine functions in implantation by stimulating the production of LIF by the endometrium (69,71) and the production of leptin and its receptor (70), by increasing the expression of the integrin β3 subunit, and by playing a fundamental role in decidualization (71,83). A deficiency in the IL-1 system in mice does not impair reproduction; however, implantation failure results from antagonizing the biological effect of IL-1 (83).
The Evolution of Anticancer Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In recent years there has also been a resurgence of interest in ethnopharmacology (also known as ethnopharmacy or ethnobotany), the study of plant materials or other natural products that are used by local communities as a traditional cure for a particular disease. The assumption is that these materials may contain an active constituent that can be identified, purified, and obtained in large amounts (by extraction or synthesis) for further studies. One recent example of the success of this approach was the identification of a novel agent now used for the treatment of proliferative skin disorders, including nonmelanoma skin cancers. Researchers at the University of Birmingham (UK) and the company Peplin Ltd (Brisbane, Australia) discovered a new agent (initially known as PEP005 or 3-Angelate) in the sap of the weed Euphorbia peplus (also known as petty spurge or milk weed) which had a history of community use for the “folklore” treatment of corns, warts, and other skin lesions such as skin cancer. The researchers isolated ingenol as the active agent, and showed that it was 100 fold more cytotoxic toward certain tumor cells in vitro than healthy cells. Furthermore, evidence was obtained that it may work by activating the protein kinase C pathway, thus inducing the interleukin decoy receptors IL1R2 and IL13RA2 and triggering apoptosis. In 2004, two INDs were filed with the FDA for the clinical development of ingenol mebutate (PicatoTM) for solar keratoses and basal cell carcinoma. In 2009, Peplin Ltd was acquired by the pharmaceutical company Leo Pharma which specializes in dermatological products, and FDA approval for the topical treatment of actinic keratosis was obtained in 2012. Given this example of successful drug discovery and development, it is possible that more novel anticancer agent leads may be derived from natural product sources in the future.
The interleukin-1 family cytokines in psoriasis: pathogenetic role and therapeutic perspectives
Published in Expert Review of Clinical Immunology, 2021
Upon ligand binding and activation, receptor complexes initiate intracellular signaling cascades driven by NF-KB and MAPK dependent pathways [10]. As a result, pro-inflammatory gene expression takes place via MyD88, IRAK and TRAF6 dependent signaling mechanisms. Distinct mechanisms to restrain IL-1 cytokines have been described: IL-1Ra and IL-36Ra bind to IL-1R1 and IL-36R, respectively, inhibiting ligand interaction and receptor assembly. IL-1R2 inhibits the activity of IL-1α and IL-1β by sequestering these ligands (intra and extracellularly). Extracellularly, IL-18 binding protein (IL-18BP) and sST2 (a soluble form of IL-33R) bind to their respective cytokines with extremely high affinity [13]. Lastly, IL-38 has been found to act as an inhibitor of IL-36R, similar to IL-36Ra, although inhibiting its action at lower concentrations [10]. The recently discovered surface receptors IL-1R8 (TIR8, SIGIR), IL-1R9 and IL-1R10 (TIGIRR2 and TIGIRR1) provide further negative regulation [10].
Improving cancer immunotherapy by targeting IL-1
Published in OncoImmunology, 2021
Zhilan Xiao, Shubhra Singh, Manisha Singh
Although inflammation helps eliminate pathogens and heals injuries, it can induce long-lasting disorders like autoimmune diseases, asthma, and cancers. Interleukin-1 (IL-1) is a well-known inflammatory cytokine that can cause sterile inflammation and infection-induced inflammation. IL-1 is also associated with tumor invasiveness and metastasis. The two forms of IL-1, IL-1α and IL-1β, are derived from different genes but are functionally similar, and both bind to IL-1 receptor type 1 (IL-1R1).1 However, other receptors, such as IL-1R2, can act as decoy receptors and bind to pro-IL-1, thus preventing it from being cleaved by proteases and released as the active form.2 Furthermore, IL-1 receptor antagonist binds to IL-1R1, thereby inhibiting its activation.3 IL-1 has been associated with decreased survival of patients with melanoma,4 and endogenous IL-1 facilitates the growth of human melanoma.5 However, the role of IL-1 in suppression of anti-tumor immunity is not well studied.
Corticosterone and progesterone differentially regulate HPA axis and neuroimmune responses to stress in male rats
Published in Stress, 2020
Cara M. Hueston, Terrence Deak
Within the BNST, significant effects of injection/surgical condition [F (2, 39) = 69.26, p < 0.001], stress [F (1, 39) = 71.71, p < 0.001], and an interaction effect [F (2, 39) = 50.11, p < 0.001] on IL-1 expression were observed. Once again, footshock had no effect on IL-1 gene expression in sham-operated rats, but footshock increased IL-1 in ADX rats, an effect that was attenuated by CORT + PROG injection (Figure 7(G)). IL-1R2 was significantly increased by stress [F (1, 35) = 28.24, p < 0.001] and a trend for an effect of injection/surgical condition [F (2, 35) = 3.24, p = 0.051] was observed. The interaction was also significant [F (2, 35) = 3.74, p < 0.05], with ADX attenuating the IL-1R2 response to footshock, which was then reinstated after injection with CORT + PROG (Figure 7(H)). Footshock increased BNST c-fos [F (1, 38) = 110.65, p < 0.001] as did ADX in the absence of CORT + PROG [F (2, 38) = 6.50, p < 0.01], although no interaction effect was observed ([F (2, 38) = 2.10, p > 0.05]; Figure 7(I)). No change in BNST β-Actin expression with injection/surgical condition [F (2, 38) = 0.25, p > 0.05], stress [F (1, 38) = 1.80, p > 0.05], or the interaction [F (2, 38) = 0.62, p > 0.05] was observed (see Supplementary Figure 1).