Interleukin 33 (IL-33), is a member of the IL-1β superfamily and of the so-called “alarmin” family. Its receptor is represented by IL-1 receptor-like 1 (IL1RL1) or ST2 [1]. Four IL-33 isoforms exist, the isoform 1, also termed “canonical IL-33″ is composed of 270 amino acids including an NH-terminal domain termed the “nuclear domain” that mediates IL-33 translocation, a central domain and an active COOH-terminal that is termed the “IL-1-like cytokine domain”. The other isoforms are shorter compared to the “canonical” IL-33 [2], [3]. It is a multifaceted cytokine, plays a pivotal role in various biological processes, making it a subject of extensive research and intrigue in the field of immunology. It is expressed not only in nonhematopoietic cells, including fibroblasts, epithelial cells, and endothelial cells, but also in cells of hematopoietic origin, particularly macrophages and dendritic cells [4]. Notably, nuclear IL-33 serves as a marker of endothelial cell quiescence, underscoring its importance in regulating the immune system.

[5]. This cytokine acts as a key regulator, effectively putting the brakes on proinflammatory nuclear factor-kappa B (NF-κB), thereby modulating chromatin compaction by promoting nucleosome-to-nucleosome interactions. IL-33's influence extends to the realm of innate and acquired immunity through its binding to the membrane-bound ST2 molecule (ST2L) of the IL-33R complex, which is expressed on various immune cells, such as Th2 cells, mast cells, natural killer cells, myeloid cells, and dendritic cells [6], [7], [8], [9].

Its effect on the immune system is diverse; IL-33 is known to promote Th2 immune responses, polarization of alternatively activated M2 macrophages [6] and the activation of newly identified Type 2 innate lymphoid cells (ILC2) that produce key cytokines in response to IL-33 [10], [11], [12], [13]. However, IL-33 could activate Th1, NK, NKT and CD8 1 T cells under certain pathophysiological conditions. IL-33 is constitutively expressed in many human tissues [14] where it is localized into the cell nucleus acting as transcriptional modulator and can have both pro-inflammatory or anti-inflammatory effects dependent upon the local microenvironment and stimuli [15]. IL-33 is expressed in several lung structural cells such as bronchiolar epithelial cells, endothelial cells and lung fibroblasts.

IL-33's role in inflammation is far from one-dimensional, as it has been found to have a dual role in inflammatory disorders. In the quest to understand the origins of IL-33, immunohistochemical examination of lung tissue samples from patients with adenocarcinoma could shed light on its presence in bronchial epithelial and vascular endothelial cells, in lung tissue cancerous lesions. These findings might underscore the intricate involvement of IL-33 in various physiological and pathophysiological conditions. For this reason, we conducted a pilot study about the immunohistochemical expression of IL-33 in surgical specimens (neoplastic and nonneoplastic peripheral lung tissues) of stage 1 o 2 lung adenocarcinoma received after kung resection surgery from the Unit of Anatomical Pathology of the University Hospital of Messina, Italy.