The anthroponotic aspects of CL show characteristics of the disease such as its complexity, seen, for example, in the variations in the clinical forms and presentation of the lesions, which are mainly highlighted in the New World. Other aspects such as the individual's immune status, parasite load and the species of Leishmania also explain the broad spectrum of the disease in the region . Among these, the activation of the immune system during the response to Leishmania infection is crucial not only for the outcome of the disease, but also seems to be associated with the effectiveness of the treatment with pentavalent antimonials. It is known, for example, that the use of antimonials improves the phagocytosis capacity of monocytes from infected patients, although it is not yet clear whether it is a direct or indirect mechanism of the drug [20, 21]. Although poorly understood, the role of some IL-1 cytokines has been shown to be important in the progression of CL pathogenesis in humans.
After three days of PBMC stimulation, we observed higher levels of IL1A expression and IL-1β protein quantifications in cells from patients with active and healed lesions, even in the absence of stimulation. Some data suggest that such cytokines are important for the activation of a Th1 response, CD4 T cells and IFN-γ production [22, 23], although they are also associated with dysregulation of the immune response [24, 25]. Our results suggest not only the stimulation capacity of L. braziliensis to direct an inflammatory response, but also that patients who underwent the treatment seem to present a resistant immune response after a new recognition of cells to Leishmania antigens, thus contributing to the cure and protection [26, 27]. This maintenance of immunological memory helps to explain the ability to produce inflammatory cytokines after stimulation by patients with CL, even after a long healing time [28, 29].
In the analysis of protein expression, the quantitation levels of IL-1β in both groups of patients before antigenic stimulation may indicate a persistent production during and after infection. On the other hand, lower IL-1α protein levels without stimulation can be observed since it is considered an “alarm” cytokine, which is restricted to the interior of the cell and is released after tissue damage and injury .
The inhibition behavior of IL1RN, a gene that encodes the protein that antagonizes the action of IL-1α and IL-1β agonists, is opposed to the elevation of such inflammatory cytokines. This may explain their strong role in the Th1 resistance response driven by L. braziliensis antigens, enabling them to play their role in inflammation and activate the immune cascades in response to the pathogen. Corroborating this, Dos Santos et al. (2017)  demonstrated in their study that L. braziliensis induces lower levels of IL-1Ra in a human monocyte lineage than L. amazonensis, evidencing a more inflammatory profile of this species.
These results also showed that, after restimulation, cells from patients who had CL and underwent the treatment expressed significantly less IL1RN, indicating that the rate of bioactive IL-1 cytokines capable of binding to the receptor is probably higher in these individuals . The IL18 significant reduction, seen mainly in the AT group, also contributes to the hypothesis that the absence of IL-18 is associated with attenuation of LC progression, perhaps due to the increase in the soluble IL-18 inhibitor receptor (IL-18BP), a target yet to be investigated in CL . Although there are still no studies evaluating IL-18 in L. braziliensis infection, much less in humans, its role in CL associated with lesions and greater severity in mice has already been observed . Furthermore, our data may indicate that the IL18 transcriptional activity decrease may be a biomarker that signals a good prognosis and response to treatment, being a cytokine sensitive to therapy with Glucantime®.
On the other hand, we see evidence that there is a balance of the inflammatory response owing to the induction of IL37 expression in response to L. braziliensis, whose protein product is known to inhibit the production of cytokines such as IL-1α, IL-6 and TNF, in addition to its production being dependent on an inflammatory stimulus [33, 34]. Although IL-37 secretion was not significantly detected in stimulated PBMCs, which can be explained by the marked presence of this protein in the cytoplasm of these cells , the increase in the number of copies of its mRNA provides clues that it plays its anti-inflammatory role in the pathogenesis caused by L. braziliensis. This data may be promising for therapeutic approaches or for use as a biomarker that signals exacerbated inflammatory activity.
Thus, we observed an important regulation of the production of IL-1 family cytokines against L. braziliensis, a parasite with immunogenic potential aimed at inducing an intense inflammatory response, as well as the role of antimonial therapy in the attenuation of IL-18, which appears to contribute to lesion healing. Our findings contribute in elucidating the participation of the IL-1 family and the still little-known role of IL-18 in CL susceptibility, as well as the regulatory role of IL-37 in response to Leishmania, which was not yet known.