*Article Bitis arietans* **Snake Venom and Kn-Ba, a Snake Venom Serine Protease, Induce the Production of Inflammatory Mediators in THP-1 Macrophages**

**Ângela Alice Amadeu Megale 1,\*, Fabio Carlos Magnoli 1, Felipe Raimondi Guidolin 1, Kemily Stephanie Godoi 1, Fernanda Calheta Vieira Portaro 2,\* and Wilmar Dias-da-Silva 1,\***


**Abstract:** *Bitis arietans* is a snake of medical importance found throughout sub-Saharan Africa and in savannas and pastures of Morocco and western Arabia. The effects of its venom are characterized by local and systemic alterations, such as inflammation and cardiovascular and hemostatic disturbances, which can lead to victims' death or permanent disability. To better characterize the inflammatory process induced by this snake's venom, the participation of eicosanoids and PAF (platelet- activating factor) in this response were demonstrated in a previous study. In addition, edema and early increased vascular permeability followed by an accumulation of polymorphonuclear (PMN) cells in the peritoneal cavity were accompanied by the production of the eicosanoids LTB4, LTC4, TXB2, and PGE2, and local and systemic production of IL-6 and MCP-1. In this context, the present study focused on the identification of inflammatory mediators produced by human macrophages derived from THP-1 cells in response to *Bitis arietans* venom (BaV), and Kn-Ba, a serine protease purified from this venom. Here, we show that Kn-Ba, and even the less intensive BaV, induced the production of the cytokine TNF and the chemokines RANTES and IL-8. Only Kn-Ba was able to induce the production of IL-6, MCP-1, and IP-10, whereas PGE2 was produced only in response to BaV. Finally, the release of IL-1β in culture supernatants suggests the activation of the inflammasomes by the venom of *Bitis arietans* and by Kn-Ba, which will be investigated in more detail in future studies.

**Keywords:** *Bitis arietans* venom (BaV); Kn-Ba; inflammation; cytokines and chemokines; PGE2; THP-1 macrophages

**Key Contribution:** Inflammation is closely related to the development of local and systemic deleterious effects due to snake envenomation. Therefore, comprehension of the molecular mechanisms involved in this process is a valuable tool to establish efficient complementary therapies. In this context, this study showed, for the first time, that BaV and Kn-Ba induced the production of different inflammatory mediators, such as cytokines, chemokines, and lipid mediators by THP-1 macrophages. Among these mediators, the production and release of the cytokine IL-1β must be highlighted, as it indicates the possible involvement of inflammasomes in *Bitis arietans* envenomation.
