**1. Introduction**

LiTCTP is a protein from the Translationally Controlled Tumor Protein (TCTP) family that was found in the *Loxosceles intermedia* brown spider venom, initially in a cDNA library of the *L. intermedia* venom gland and confirmed in the transcriptome analysis of the venom gland [1,2]. Although it represented only 0.4% of the toxin-related transcripts, it was positively identified by immunodetection in the whole venom of di fferent *Loxosceles* species (*L. intermedia*, *L. gaucho*, and *L. laeta*) [3], which indicates its biological conservation and importance. TCTP proteins are known as histamine releasing factors (HRF) and activators of mast cells and basophils triggering the release of histamine [4,5]. Mast cells are intimately involved in allergic and anaphylactic reactions, and an increasing body of evidence involves these cells and their mediators in the pathophysiology of inflammation [6]. *Loxosceles* venoms are responsible for severe skin lesions at the bite site, characterized by intense inflammatory content, which can evolve to necrotic conditions [7,8]. Hypersensitivity or even allergic reactions are also reported as clinical features of Loxoscelism [9,10]. Mast cells were already mentioned as involved in biological responses evoked by *Loxosceles* venom toxins, as inflammatory response was partially reduced in compound 48/80-pretreated animals [11]. Previous study of LiRecTCTP, the recombinant isoform of LiTCTP, showed this toxin increases microvascular permeability of skin vessels, causing a di ffuse pattern of dye leakage. Moreover, LiRecTCTP induced paw edema, which reached its maximum after 5 min of inoculation (an early e ffect compared to dermonecrosis) [2]. TCTP was already described as a putative therapeutical target in asthma and allergy due to its pro-inflammatory extracellular e ffects [5,12]. Herein, we studied the participation and e ffects of LiRecTCTP toxin in the biological histaminergic and inflammatory response observed in Loxoscelism. LiRecTCTP was also studied in combination with the well-known LiRecDT1 Brown spider toxin, a recombinant isoform of phospholipase-D (PLD) of *L. intermedia*. LiRecDT1 can cause the majority of whole venom-induced effects in vitro and in vivo. Meanwhile, LiRecTCTP was shown to enhance the biological response to LiRecDT1, pointing to its contribution to the exacerbated inflammatory response observed clinically in the patients. Our findings strengthen the idea of inhibition of LiTCTP and mast cell activation e ffects as promising therapeutic approach to reduce the inflammatory events responsible for the main symptoms in cutaneous Loxoscelism.
