Interleukins form an integral part of Immune response by an organism. There is always an ideal M1/M2 balance which drives a species-specific response. Evolution has standardized these responses and made Livestock resilient to many diseases to help protect from farming losses.
Over the years, production driven stressors have induced certain imbalances which are either nutritionally driven or effected by genetic selection. This skewed M1/M2 balance has resulted in an oxidative tendency, especially in Poultry. Surrounding Stressors during production compound these factors resulting in reduced performance of the birds and increase in Susceptibility to Cytokine storms/overreactive immune system causing high Mortality rates. We try to understand a few of the Interleukins which may prove important in correcting the balance.
Immune response and its regulation are crucial in maintaining the balance between inflammatory and non-inflammatory responses. These balances are induced by the small effector molecules, called cytokines. The cytokines help in communication between the immune cells and fight infections by alarming the innate as well as adaptive immune system. IL-10 is an anti-inflammatory cytokine that downregulates the expression of pro-inflammatory cytokines such as IFNγ, tumour necrosis factor α (TNFα), IL-1β, and IL-6 in several cell types and prevents dendritic cell (DC) maturation in part by inhibiting the expression of IL-12. Originally it was described as cytokine synthesis inhibitory factor (CSIF). IL-10 is the founding member of the IL-10 cytokine family, which includes IL-19, IL-20, IL-22, IL-24, and IL-26. (Walter, 2014)
The first phase of the monocyte response is the rapid production of TNF-α, which induces the release of other cytokines such as IL-1 and IL-6. The second phase involves the production of IL-10, which is detectable within 8 h of exposure to LPS. IL-10 down-regulates the production of inflammatory cytokine synthesis of Th1 cells and inhibits macrophage functioning NK cells, peripheral blood mononuclear cells (PBMC) and Th1 cells. IL-10 inhibits the synthesis of IFN-γ and IL-1 in Th1 cells and CD8+/ cells and strongly down-regulates the constitutive IFN-γ or IL-4 induced MHC class II Ag expression. IL-10 production is also induced by pathogen-derived products that activate monocytes and other lymphocytes. The receptor of the IL-10 molecule belongs to the cytokine receptor family type 2. They are trans-membrane glycoproteins whose extracellular domains consist of 21 aa, comprising two tandem fibronectin type III domains. (Conti et al., 2003)
The cellular response to IL-10 depends on the engagement of the IL-10R and intracellular signalling cascades occur through a heterodimeric receptor. The IL-10 receptor is composed of two subunits: the high-affinity IL-10Rα and IL-10Rβ. When the IL-10 binds to the receptor, it causes the assembly of the IL-10Rα and IL-10Rβ chains. This, in turn, allows the phosphorylation of JAK1 associated with the IL-10Rα subunit and of tyrosine kinase 2 (TYK2) associated with the IL-10Rβ subunit. These kinases further phosphorylate two functional tyrosine residues on the intracellular domain of the IL-10Rα, needed for the recruitment of STAT3. STAT3 upon phosphorylation translocates to the nucleus further initiating IL-10 mediated anti-inflammatory response. (Saraiva et al., 2020)
The role of IL-10 is also associated with Eimeria infections that cause coccidiosis in chickens and diseases like Inflammatory Bowel Disease (IBD) in humans and other animal models, also causing Cancer, Diabetes, etc. In a study, it was found that increased IL-10 in the presence of pathogens causes the inhibition of pro-inflammatory cytokines which helps the pathogens to evade host immune response whereas in knock-out animal models for IL-10, administering IL-10 or anti-IL-10 antibody helps in disease prevention. For example, it was proved that the protective effects of anti-IL-10 prevented reduced body weight due to the Eimeria challenge. One possible mechanism by which anti-IL-10 could be protective against reduced body weights due to the Eimeria challenge was that anti-IL-10 may be served as a protectant against intestinal mucosa dysfunction and decreased nutrient absorption during the Eimeria challenge (Arendt et al., 2016).
In another study, IL-10-deficient and IL-10R2-deficient mice develop chronic intestinal inflammatory disorders and are successfully treated by administration of IL-10, indicating the role of IL-10 in the development of inflammatory bowel disease (IBD) and the effect of IL-10 in the treatment of IBD. Transfer of CD4+ T cells (which produce IFN-γ and TNF-α) into severe combined immune-deficient (SCID) mice causes IBD, and administration of CD4+ T cells (which produce IL-4 and IL-10) or mIL-10 prevents the development of IBD.(de Rijn et al., 2002)
Cytokines are the key effector molecules that play a dominant role in maintaining a balance between innate and adaptive immune systems. IL-10 is an anti-inflammatory cytokine that plays a crucial role in pathogenesis and disease conditions. IL-10 production can be induced by various immune cells and it downregulates the expression of pro-inflammatory cytokines by inhibiting the proliferation of specific immune cells which causes inflammation. Receptor-ligand interactions are caused when IL-10 binds to the heterodimeric receptor present in the target cells, which leads to the cascade of events including phosphorylation of transcription factors and induce gene expression that mediates an anti-inflammatory response. IL-10 also plays a role in the growth regulation of chickens as well as in animal models, which shows IL-10 has great importance in therapeutics. IL-10 with many biological effects and its mechanism in the immune system, helps us to understand its impact on the health of the individual organism. Thus, IL-10 may prove to be the missing key that modulates a measured immune response.
Author: Bhagyalaxmi Junnuru
Bibliography:
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