Interleukin 10 mutant zebrafish have an enhanced interferon gamma response and improved survival against a Mycobacterium marinum infection

Abstract

Tuberculosis ranks as one of the world’s deadliest infectious diseases causing more than a million casualties annually. IL10 inhibits the function of Th1 type cells, and IL10 deficiency has been associated with an improved resistance against Mycobacterium tuberculosis infection in a mouse model. Here, we utilized M. marinum infection in the zebrafish (Danio rerio) as a model for studying Il10 in the host response against mycobacteria. Unchallenged, nonsense il10e46/e46 mutant zebrafish were fertile and phenotypically normal. Following a chronic mycobacterial infection, il10e46/e46 mutants showed enhanced survival compared to the controls. This was associated with an increased expression of the Th cell marker cd4-1 and a shift towards a Th1 type immune response, which was demonstrated by the upregulated expression of tbx21 and ifng1, as well as the down-regulation of gata3. In addition, at 8 weeks post infection il10e46/e46 mutant zebrafish had reduced expression levels of proinflammatory cytokines tnfb and il1b, presumably indicating slower progress of the infection. Altogether, our data show that Il10 can weaken the immune defense against M. marinum infection in zebrafish by restricting ifng1 response. Importantly, our findings support the relevance of M. marinum infection in zebrafish as a model for tuberculosis.

Concurrent metformin and silibinin therapy in diabetes: assessments in zebrafish (Danio rerio) animal model

“…Th1 (interferon-gamma) also suppresses specific antigen response by blocking the inflammatory response induced by cytokines such as inter-leukine-10 (IL-10) [37]. It seems that by suppressing IFN-γ production, the suppression of this cytokine on TH17 cells also diminishes, resulting in an increase in IL17 production [16].As shown by Fig. 5, the highest expression of interferon gamma gene was observed in the control and glucose-containing control groups (G-CTRL, G + CTRL) (p < 0.05).…”

“…This study indicated that beta-cell number could be significantly increased using metformin [14].Inflammatory biomarker genes are found in diabetic and obese individuals, and these biomarkers can predict the progression of type 2 diabetes. In the present study, we investigate the possibility of tracking the inflammation in diabetes type 2 induced model of Zebrafish in the intestine and expression of TNF-α [15], IFN-γ [16] and IL-1β genes [17] by chemical (metformin) and herbal (Silymarin) alone and as combined drugs. Indeed, we intend to introduce a novel herbal and chemical combination compound to reduce the effects the possible inflammation caused by hyperglycemia due to high concentration of glucose uptake in zebrafish.…”

Zebrafish IL-4-like cytokines and IL-10 suppress inflammation but only IL-10 is essential for gill homeostasis

“…No significant morphological changes were observed in the gills of il4/13a −/− , il4/13b −/− or il4/13a;b −/− fish compared to wildtype (Figure 4A), suggesting that loss of functional IL-4/13A and IL-4/13B does not affect tissue morphology despite a shift toward type 1 immunity. For comparison, we examined the gills of il10 e46/e46 mutants lacking functional IL-10, which have also been reported to shift towards type 1 immune responses (38). A thickening of the gill arch and filaments, as well as lamellar epithelial changes were detected in the absence of functional IL-10, indicating a role for this cytokine in maintaining gill homeostasis in adult zebrafish.…”

“…An anti-inflammatory role for IL-10 has been previously shown in carp (64) and in zebrafish gut (65). Moreover, suppression of Th1 cell response and cytokine production was reported in a zebrafish M.marinum model (38). For the first time to our knowledge, we addressed the function of zebrafish IL-10 in the gills and demonstrated its importance in preventing inflammation in this mucosal tissue.…”

Teleost contributions to the understanding of mycobacterial diseases

“…M. marinum induced expression of IL-10 has been observed in goldfish primary kidney monocytes and macrophages (Grayfer et al, 2011), although no apparent increases of IL-10 were observed in spleen or kidney tissues during infections (Hodgkinson et al, 2012), and introduction of recombinant IL-10 did not alter the viability of M. marinum within goldfish phagocytes (Hodgkinson et al, 2012). In zebrafish, IL-10 mutants showed enhanced survival and enhanced interferon gamma response following chronic M. marinum infection (Harjula et al, 2018).…”