Interleukin-1 receptor antagonist: a promising cytokine against human squamous cell carcinomas

Abstract

Inflammation, especially chronic inflammation, is closely linked to tumor development. As essential chronic inflammatory cytokines, the interleukin family plays a key role in inflammatory infections and malignancies. The interleukin-1 (IL-1) receptor antagonist (IL1RA), as a naturally occurring receptor antagonist, is the first discovered and can compete with IL-1 in binding to the receptor. Recent studies have revealed the association of the polymorphisms in IL1RA with an increased risk of squamous cell carcinomas (SCCs), including squamous cell carcinoma of the head and neck (SCCHN), cervical squamous cell carcinoma, cutaneous squamous cell carcinoma (cSCC), esophageal squamous cell carcinoma (ESCC), and bronchus squamous cell carcinoma. Here, we reviewed the antitumor potential of IL1RA as an IL-1-targeted inhibitor.

Keywords: Gene polymorphisms; Interleukin-1 family; Interleukin-1 receptor antagonist; Squamous cell carcinoma; Tumor microenvironment.

Fig. 1

IL1A(A), IL1B(B), IL1RA(C), IL1R1(D), IL1R2(E) and IL1RAP(F) mRNA expression in normal human tissue plotted as transcripts per million (TPM). Data were obtained from Human Protein Atlas dataset available from proteinatlas.org.

Fig. 2

Structures and functions of the IL1R complex: (1) IL1B forms a high-affinity trimeric complex with IL1R1 and IL1RAP after binding. (2) The complex triggers IL-1 signaling through the NF-κB pathway. (3) IL1RA cannot generate signals when in contact with IL1R1. (4) IL1R2 is a decoy target and has a high affinity with mature IL1B. (5) IL1R2 sends no signals, which make it acts as a scavenger. (6) In the extracellular space, SIL1R2 can either directly attach to IL-1 or form a complex with soluble IL1RAP, thus preventing IL1B from binding to IL1R1 for signaling.

Fig. 3

Structures and functions of IL1A and ICIL1RA. (1) Parts of proIL1A are cleaved by Calpain into the SIL1A which can be secreted during cell necrosis and IL1NTP. (2) IL1NTP can be transported to the nucleus during the inflammatory state to activate NF-κB and AP-1. (3) Other parts of proIL1A are methylated and anchored to the cell membrane to abolish the invasiveness of malignant cells. (4) The role of ICIL1RA is to neutralize the active intracellular forms of IL1A and suppress the carcinogenesis in exposed epithelial cells.

Fig. 4

Structures and functions of IL1B and SIL1RA. (1) When the cell is stimulated, caspase-1 processes proIL1B into a mature form of IL1B, which will be secreted to the TME. (2) IL1B promotes tumor angiogenesis through its interaction with VEGF, EPC, and myeloid cells. (3) IL1B promotes tumor proliferation by inducing inflammatory molecules such as MMP, heparinase, and chemokines. (4) SIL1RA suppresses IL1B in the TME by competing with IL1B for binding to IL1R1. (5) (6) The interaction between the IL-1 family and the IL1R family.

Fig. 5

Expression profiles of IL1RN in various types of SCCs. Among them, IL1RN expression decreases significantly in SCCHN, compared to that in the normal tissue (p-value = 2.6E-07) (A). In contrast, IL1RN expression increases significantly in cervix squamous cell carcinoma (p-value = 1.26E-08) (B), ESCC (p-value = 7.29E-01) (C), lung squamous cell carcinoma (p-value = 1.87E-05) (D). Data are obtained from the UALCAN dataset, which is the Cancer Genome Atlas (TCGA) database visual web portal [142]. And p-value <0.05 indicates statistically significant.