The mechanisms of the anti-inflammatory effect of apigenin are persist unclearly. We studied the effects of apigenin on LPS-induced inflammation in male rats. Our results demonstrate that apigenin has anti-inflammatory effects in LPS treated rats, partially due to decreasing the IL-1β, IL-6, and TNF-α pro-inflammatory cytokine levels. This suppression effect has not a dose-dependent pattern. Our result showed that, compared to dexamethasone, the anti-inflammatory effect of apigenin is feeble, but 24 hours after induction of inflammation, apigenin has almost the the same anti-inflammatory effect as dexamethasone.
The injection of LPS, a component from the cell wall of gram-negative bacteria, is a relatively well-characterized model usage for activation of the immune system. LPS binds CD14 and Toll-like receptor 4 and can activate transcription factors, such as NF-κB. This transcription increases the production of pro-inflammatory cytokines (3).
IL-1β and IL-6 are a proinflammatory cytokine that regulates various physiological processes. Both play a vital role in the acute phase response and transition of acute inflammation to a chronic state. Evidence has accrued to suggest that dysregulation of IL-6 production is a major contributor to the pathogenesis of chronic inflammatory and autoimmune diseases. These Interleukins are made by white blood cells that interact with innate immunity and acquired immunity (15). Sepsis is one of the most critical and prevalent problems of infants, especially in low premature infants. Therefore, recognition of this disease is very important. Kocabaş et al. (2007) studied the role of IL-6 and TNF-α in the diagnosis of neonatal infections. The mean serum IL-6 and TNF-α levels were significantly higher in septal neonates before treatment than healthy neonates (16). Also, Boskabadi et al. (2013) evaluated the serum level of IL-6, 8, and 10 as the primary markers of infant infections. Their results showed a significant difference between the case and control groups at the level of IL-6, 8, and 10 (P < 0.001). IL-6 was the highest value for prediction of infection than other cytokines (17).
As an herbal compound, Flavonoids have beneficial effects on reducing inflammation and oxidative stress (13). Understanding the function and regulation of the prognostic factors involved in inflammation may provide new strategies for treating inflammatory diseases. Phytochemicals are natural ingredients with anti-inflammatory function which much attention is being paid to their benefits besides low toxicity and side effects. Recently, the use of herbal products to treat inflammatory diseases has increased as a new method, and the herbs medications have played a vital role in health care (18). The focus of drug discovery efforts has shifted from the lab bench to nature, and herbal medicines are still a rich source for the development of new drugs (19, 20). However, major barriers to the development of herbal medicines in the development of new drugs are the lack of scientific evidence of functional mechanisms, unknown toxicity, and drug interactions (21). Our findings in the present study provide important scientific evidence for the potential use of Apigenin as a therapeutic agent for inflammatory diseases. Therefore, our study focuses on the action of apigenin bioflavonoids in reducing pro-inflammatory cytokines. The apigenin is a beneficial molecule, mostly found in fruits and vegetables. The molecular and cellular effect of apigenin based on the recent studies origins through modulation of the gene expression of the cyclooxygenase, lipoxygenase, nitric oxide synthase, several inflammatory cytokines and the mainly affects the mitogen-activated kinase (MAPK) and NF-κB and activator protein1 (AP-1) transcription factors that regulate many important biological and pathological processes (22). Due to their fundamental role in the intracellular signaling network and related transcription pathways, these factors have an appropriate target for therapy in inflammatory diseases (23). In this regard, Wang et al. (2015) showed that oxidative low-density lipoprotein (ox-LDL) maintains the survival of macrophages and induces secretion of protein-induced inflammatory cytokines to trigger in mice atherosclerosis. Prescription of apigenin can be reducing the number of foam cells and atherosclerosis, accompanying with reducing serum levels of TNF-α, IL-1β, IL-6. In fact, reducing macrophage-secretion of pro-inflammatory cytokines caused reduction of the inflammation and was followed by atherosclerosis (24). In this context, Weicheng et al. (2016) was studied the molecular mechanisms of inflammatory cytokines suppression of apigenin in RAW 264.7 macrophage cells, which stimulated by LPS. The researchers were reported that apigenin suppressed production of NO, PGE2, and TNF-α in RAW 264.7 in a dose-dependent manner. Additionally, apigenin inhibits the release of LPS-induced mRNA of iNOS, COX-2, and TNF-α. Treatment with apigenin reduced the transfer of c-Jun to the nucleus and reduced the activation of AP-1 by inhibiting MAPK and extracellular signal-regulated kinase (ERK) phosphorylation (25). Also, the protective effects of apigenin-enriched dietary were studied in a chronic colitis model induced by DSS in mice. The dietary apigenin supplementation in dietary decreased the damage signs of colitis, also reduced IL-1β and TNF-α proinflammatory cytokine secretions in primary LPS-stimulated solenocytes. Furthermore, the decreasing of IL-1β and IL-18 cytokine levels as a consequence of the regulation cleaved caspase-1 and caspase-11 enzymes (26, 27). Almost similar to our work, Karamese et al. (2016) investigated the protective effects of apigenin in a polymicrobial sepsis rat model. Based on their studies results, early treatment with apigenin significantly reduces the rate of inflammatory cells (28). The apigenin effects include inhibition of NF-κB pathway, suppression of inflammatory cytokines, and induction of anti-inflammatory cytokine production. According to evidence, inflammation may contribute to the pathophysiology of depression. So, its potential antidepressant activity was examined on LPS-induced depressive-like behavior in male mice. Pre-treatment with apigenin (25 and 50 mg/kg, IP) or fluoxetine (standard antidepressant drug) prevented LPS-induced abnormal behavior and attenuated production of IL-1β and TNF-α. Also, apigenin significantly reduced the expression of iNOS and COX-2 at both levels of mRNA and protein by modulating NF-κB in the prefrontal cortex (29, 30). This study evaluated the effect of pre-treatment with low doses of apigenin on the serums level of proinflammatory cytokine in LPS-stimulated rats. Our results were similar to the mentioned results of other studies. Further studies are needed to make decisions about choosing the most appropriate dosage, as well as for deciding how to administrate flavonoids to humans and obtaining authorization from the Food and Drug Administration of American (FDA). It needed to be given to allow for researchers to designed clinical trials and interventions, and in this way, there is a need to further studies to confirm or refute the use of this compound for humans.