Familial Mediterranean Fever (FMF) is typically inherited in an autosomal recessive pattern and it is characterized by recurrent episodes of fever along with abdominal pain, chest pain, joint pain, and sometimes a characteristic rash [1]. The disease is the most common monogenic autoinflammatory disease [2] and has a high prevalence among Sephardic Jews, Armenians, Turks, and Arabs [3]. FMF results from genetic mutations in the MEFV gene, responsible for producing pyrin, a protein mainly found in innate immune cells [4]. These mutations trigger caspase-1 and prompting the release of interleukin-1β (IL-1β) which a crucial factor in the pathogenesis of the disease [5]. Pyrin dysfunction leads to abnormal production of IL-1β and IL-18 [6], [7], activating nuclear factor kB pathways and causing overexpression of tumor necrosis factor-alpha (TNF- α) and IL-6 [8], [9]. In individuals with FMF, attacks are associated with elevated levels of proinflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF- α [10]. Monocytic cells secrete IL-1β, a significant proinflammatory mediator that initiates inflammatory reactions in the majority of tissues. To become biologically active, it must be processed by inflammasomes [11]. Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammatory dysregulation is characterized by mutations in the MEFV gene [12]. It is widely recognized as the most well-studied inflammasome due to its capacity to produce IL-1β when exposed to microbial and metabolic challenges.

Src family kinases (SFKs) are from the protein tyrosine kinase group, which are the main regulators of important cellular processes, and consist of members of Yes, Src, Blk, Fyn, Lck, Lyn, Fgr and Hck [13]. It has been revealed that SFKs are also associated with inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) [14]. Pemphigus [15] and Behçet [16] that imply they may play important roles in signaling pathways related to inflammation and play an active role in inflammatory diseases and immune response [16], [17], [18], [19], [20]. However, the role of SFKs in regulation of IL-1β, IL-6, IL-8, TNF-α and NLRP3 has not been fully addressed in FMF yet.

Lipopolysaccharide (LPS) is a primary element found in the outer cell wall of gram-negative bacteria and is responsible for triggering acute inflammation. Its inflammatory activity is mediated through binding to toll-like receptor-4 (TLR4) [21]. Immune system cells are activated by LPS [22], [23]. It stimulates an inflammatory reaction by increasing the synthesis of proinflammatory cytokines and chemokines, such as TNF-α, IL-6, and IL-8 [24], [25]. It has been documented that LPS stimulation activates SFKs [19]. They are crucial for the immunological response as well. Numerous investigations have also demonstrated that SFKs are essential for a number of LPS-guided proimflammatory cytokines and associated signaling pathways [16], [19], [25] and PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo(3,4-d(pyrimidine) has been recognized for its strong and targeted inhibition of the SFKs [26].

In this research, we invastigated the key role of the SFKs that drive proimflamatory cytokines and related signaling in FMF patients. It has been demonstrated that Lck is overexpresed in peripheral blood mononuclear cells (PBMC) of FMF patients. We also observed that there is an aberant expression of the IL-1β by activation of SFKs and it reduced by inhibition of it in FMF patients.