The Role of Interleukin-1 cytokine family (IL-1β, IL-37) and interleukin-12 cytokine family (IL-12, IL-35) in eumycetoma infection pathogenesis

Mycetoma is a neglected tropical disease, endemic in many tropical and subtropical regions, characterised by massive deformity and disability and can be fatal if untreated early and appropriately. Interleukins (IL)-35 and IL-37 are newly discovered cytokines that play an important role in suppressing the immune system. However, the expression of these interleukins in patients with Madurella mycetomatis (M. mycetomatis) induced eumycetoma has not yet been explored. This study aims to determine the levels of the IL-1 family (IL-1β, IL-37) and IL-12 family (IL-12, IL-35) in a group of these patients and the association between these cytokines levels and the patients’ demographic characteristics. The present, a case-control study was conducted at the Mycetoma Research Centre, Soba University Hospital, University of Khartoum, Sudan and it included 140 individuals. They were divided into two groups; group I: healthy controls [n = 70; median age 25 years (range 12 to 70 years)]. Group II: mycetoma patients [n = 70 patients; median age 25 (range 13 to 70 years)]. Cytokines levels were measured in sera using enzyme-linked immunosorbent assay (ELISA). There was no significant correlation between the IL-1β and IL-12 levels and the lesions size and disease duration, whereas levels of IL-37 and IL-35 were significantly correlated with that. The analysis of the risk factors of higher circulatory levels of IL-37 in patients of mycetoma showed a significant negative association with IL-1β cytokine, where a unit increment in IL-1β will decrease the levels of IL-37 by 35.28 pg/ml. The levels of IL-37 among the patients with a duration of mycetoma infection ≤ one year had significantly decreased by an average of 18.45 compared to patients with a mycetoma infection’s duration of ≥ 5years (reference group). Furthermore, the risk factors of higher levels of IL-35 in mycetoma patients revealed a significant negative association with IL-12, as a unit increment in IL-12 decreases the levels of IL-35by 8.99 pg/ml (p < 0.001). Levels of IL-35 among the patients with duration of mycetoma infection ≤ one year had significantly decreased (p-value = 0.002) on average by 41.82 compared to patients with a duration of mycetoma infection ≥ five years (reference group). In conclusion, this study indicates that both IL-35 and IL-37 are negatively associated with the levels of IL-1β and IL-12 in eumycetoma mycetoma infection; and high levels of IL-37 and IL-35 may have a negative impact on disease progression. Authors Summary Mycetoma is a progressive chronic granulomatous fungal or bacterial infection that may result in massive destruction of subcutaneous tissues, muscles and bones. Mycetoma is a neglected disease which is endemic in many tropical and subtropical areas. If the disease is not treated properly, eventually it ends up with amputation and adverse medical, health and socioeconomic effects on patients and the community. Previous data suggested a crucial role of adaptive immunity in host resistance to causative agents and the disease progression. The recently identified IL-35 and IL-37 cytokines revealed an important role in immune suppression. Nevertheless, the expression of these interleukins in patients with mycetoma has not yet been investigated. Therefore, the present case-control study aimed to determine the levels of IL-1 family (IL-1β, IL-37) and IL-12 family (IL-12, IL-35) in these patients and the association between these cytokines levels and the patients’ demographic characteristics. The results of this study showed that the levels of IL-37 and IL-35 were consistently positively correlated with different diameters of mycetoma lesions as well as its duration. However, the levels of IL-1β and IL-12 were consistently negatively correlated with different diameters of lesions and the duration of mycetoma infection. The analysis of the risk factors of higher circulatory levels of IL-37 in patients of mycetoma showed a significant negative association with IL-1β cytokine. Furthermore, the risk factors of higher levels of IL-35 in patients of mycetoma revealed a significant negative association with IL-12. These findings uncover a possible the role of IL-35 and IL-37 in the pathogenesis of mycetoma and may declare their potential value in the treatment of mycetoma.