Table 1.

Summary of pathophysiological aspects of interleukins in NAFLD.

ILs	Pathophysiological Aspects in NAFLD
IL-1	The manufacture of extracellular matrix proteins, hepatocyte malfunction, necrosis, apoptosis, and the release of pro-inflammatory cytokines such TNF-α and IL-1, which ultimately result in cirrhosis and fibrosis [12]. IL-18 but not IL-1 signaling is the key initiator for liver injury in NAFLD in mice. IL-18R-dependent signaling and NLRP3 activation may be modulators of early liver damage in NAFLD [16]. Whereas Pd-l1 expression increased in NASH, IL-1β suppression boosted the hepatic expression of immunological checkpoint molecules Pd-1 and Ctla4 [17]. This inflammasome is also activated by stimulation of damage-associated molecular patterns. Following activation, the inflammasome displays caspase-1 activity, which causes the cell wall to become porous and releases IL-1 and IL-18. This procedure causes inflammatory cell death (pyroptosis) and expands the inflammatory response outside of the cell. Fibrosis is a result of the inflammatory cascade that follows [19]. The degree of lobular inflammation in the liver and NASH were related to blood levels of IL-1RA and hepatic mRNA expression of IL1RN [20]. IL-1β and IL-10 might be biomarkers for the advancement of NAFLD in both its independent course and in conjunction with HT [21]. The development of steatosis and inflammation in NASH patients is due to an excess of pro-inflammatory factors (IL-1beta, IL-6, and TNF-ɑ), and the early stage of NAFLD is comparable to that of healthy persons [22]. In this context, IL-1β, an inflammatory cytokine, plays a crucial role in initiating and perpetuating inflammation and tissue damage. The activation of IL-1β involves cytosolic machinery collectively known as the inflammasome, as well as proteases released by neutrophils. While macrophages are the primary drivers of the inflammatory response, other hepatic cells, including hepatocytes, stellate cells, and sinusoidal endothelial cells, also contribute significantly. Acute phase reactants, which are released by hepatocytes and have both pro- and anti-inflammatory properties, are a primary source of chemicals linked to damage. However, the overall effect seems to be context-dependent. On the other hand, stellate cells can control the development of regulatory T cells by producing all-trans retinoic acid and transforming growth factor (TGF)-β [27].
IL-2	The NASH group’s IL2RA expression was noticeably greater than that of the non-NASH group [29]. Infants with portal inflammation and stage 3–4 fibrosis had greater levels of soluble IL-2 receptor alpha [30].
IL-3	Undetermined
IL-4	Disruptions in lipid metabolism were significantly associated with levels of TNF-α and IL-4 [34].
IL-5	Serum IL-5 levels in NAFLD group were significantly higher than those of the control group [36].
IL-6	TNF-α, IL-6, and other pro-inflammatory cytokines are important players in the pathophysiology of NAFLD. These cytokines are also essential for the emergence of insulin resistance, which is a major component in the pathophysiology of NAFLD [25]. Furthermore, TGF-β and MCP-1 liver gene expression was significantly reduced in IL-6−/− animals, but PPAR-γ and F4/80 transcripts and proteins showed a more moderate decrease. However, in IL-6-deficient animals fed the MCD diet, lobular inflammation was decreased and the expression of important inflammatory genes was inhibited, indicating that IL-6 is essential for the related liver inflammation [38]. In animal models of NAFLD, hepatic IL-6, a major pro-inflammatory cytokine, is upregulated, and sustained elevation in mice results in systemic insulin resistance. These findings suggest that elevated hepatic IL-6 production may play a crucial role in the development of NASH, as well as in systemic insulin resistance and diabetes [39]. Pro-inflammatory cytokines, including TNF-α and IL-6, have a pivotal role in the pathogenesis of several features of non-alcoholic fatty liver disease in humans [41]. Hepatic steatosis generated by the MCD diet was exacerbated when MR16-1 blocked IL-6/GP130 signaling, although liver damage was reduced. These results imply that hepatic IL-6 signaling may increase liver inflammation but also protects against the development of hepatic steatosis [42]. A possible causative relationship between I148M-mediated sensitivity to NAFLD and increased IL-6/STAT3 activity [43]. The alterations in the blood’s concentration of soluble IL-6 receptors were linked to the advancement of NAFLD. Additionally, a strong association between alterations in soluble IL-6 receptor levels and hepatocyte and peripheral blood leukocyte death was shown [44]. The presence of hyperglycemia and hyperlipidemia may directly impact IL-6 trans-signaling, potentially contributing to the increased severity of NAFLD in individuals with concurrent diabetes [45]. Animal models indicated that increased hepatic expression of IL-6 was linked to NAFLD, the hypothesis was that IL-6 can serve as a predictor of NAFLD progression [48]. IL-6 showed an elevation specifically in NASH cases [50].
IL-7	IL-7 decreased with portal inflammation and fibrosis severity [30].
IL-8	Patients with lobular inflammation and stage 3–4 fibrosis had higher levels of IL-8 [30]. Compared to people with a normal liver, morbid obesity with NASH was associated with considerably higher levels of IL-8 [55]. While the A/A genotype in the IL-8 gene was linked to the advancement of the illness, polymorphisms in the IL-6 and IL-8 genes do not appear to have a role in the pathophysiology of NASH or liver fibrosis [56]. IL-8 plays a crucial role in systemic inflammation progression and, more importantly, contributes significantly to the escalating severity of liver disease in NAFLD [57]. In HFD-fed mice, hepatic overexpression of human IL8 stimulates neutrophil infiltration and accelerates the transition from fatty liver to NASH [58]. IL-8 was shown to be a robust predictor of enhanced fibrotic liver damage compared to recognized markers of hepatic fibrosis [60]. IL-8 levels were higher in patients with liver fibrosis among those with obesity and NAFLD having bariatric surgery [59].
IL-9	In rats with NAFLD, taurine may prevent or treat liver and ileal mucosa damage by downregulating the production of TGF-β and IL-9. These two factors may be involved in the development of NAFLD [62].
IL-10	No difference between IL-10 between NAFLD patients and controls was shown [33]. IL-10 is an independent factor associated with NAFLD [51]. IL-10 is a major regulatory factor in the pathophysiology of NAFLD, as well as in inflammatory illnesses, malignancies, and autoimmune disorders [64]. IL-10 and IL-1β may be taken into consideration as biomarkers of the severity of NAFLD [66].