The molecular mechanism of L-valine's regulation of the immune system

L-valine, as one of the essential branched-chain amino acids (BCAAs) in humans, not only participates in protein synthesis but also plays a key role in regulating the immune system by modulating the metabolic state, signaling pathways, and cytokine secretion of immune cells. Its molecular mechanisms mainly involve the following four levels:

I. Regulating Immune Cell Activity Through Metabolic Remodeling

The activation of immune cells relies on efficient energy supply and material synthesis, and L-valine can influence immune function by regulating cellular metabolic pathways:

Providing energy and raw materials for T cell activation: Upon antigen stimulation, T cells undergo metabolic reprogramming, shifting from oxidative phosphorylation to glycolysis to rapidly generate ATP. The catabolism of L-valine (transamination to form α-ketoisovalerate, which ultimately enters the tricarboxylic acid cycle) supplements mitochondrial metabolic intermediates, maintaining energy homeostasis in activated T cells. Meanwhile, its metabolites provide carbon skeletons for nucleotide and lipid synthesis, supporting T cell proliferation and differentiation. Experiments have shown that L-valine deficiency reduces the proliferation rate of CD4⁺ T cells by over 40% and impairs the differentiation of effector T cells (e.g., Th1, Th17).

Regulating macrophage polarization: M1-type macrophages (pro-inflammatory phenotype) rely on glycolysis, while M2-type (anti-inflammatory phenotype) depend more on oxidative metabolism. L-valine can promote macrophage polarization toward the M2 type by activating the AMPK signaling pathway: when L-valine is sufficient, AMPK phosphorylation levels increase, inhibiting the mTOR-HIF-1α pathway (which drives M1 polarization) while enhancing mitochondrial respiratory chain activity. This increases the secretion of anti-inflammatory cytokines such as IL-10 by 2-3 fold, reducing excessive inflammatory responses.

II. Activating Immune-Related Signaling Pathways

L-valine can regulate the functional state of immune cells by directly or indirectly acting on intracellular signaling molecules:

Activation of the mTORC1 pathway: mTORC1 is a core pathway for cells to sense nutritional signals. As an activator of mTORC1, L-valine promotes the localization of mTORC1 to the lysosomal membrane through the Rag GTPases complex, thereby phosphorylating downstream target proteins S6K1 and 4E-BP1. This process is crucial for T cell survival and differentiation: for example, L-valine-mediated mTORC1 activation can promote the differentiation of naive T cells into effector T cells while inhibiting the differentiation of regulatory T cells (Treg), enhancing the intensity of immune responses. Conversely, L-valine deficiency leads to mTORC1 inactivation, rendering T cells "anergic."

Regulation of the NF-κB pathway: L-valine can indirectly regulate the nuclear translocation of NF-κB by inhibiting the degradation of IκBα. In dendritic cells (DCs), this mechanism reduces the release of pro-inflammatory factors such as TNF-α and IL-6, avoiding excessive immune activation. In natural killer (NK) cells, moderate NF-κB activation enhances their cytotoxicity, promoting the clearance of virus-infected or tumor cells.

III. Modulating Cytokine and Immune Mediator Secretion

L-valine regulates the balance of cytokine networks by influencing the transcriptional and translational processes of immune cells:

Promoting anti-inflammatory factor expression: In macrophages, L-valine upregulates IL-10 transcription by activating the STAT3 signaling pathway. As a key anti-inflammatory cytokine, IL-10 inhibits the synthesis of pro-inflammatory factors (e.g., IL-1β, TNF-α), alleviating tissue damage in chronic inflammation or autoimmune diseases. Studies have shown that L-valine supplementation increases IL-10 levels by over 50% in LPS-induced mouse models while reducing IL-1β levels by 30%.

Enhancing secretion of immune defense-related factors: In T cells, L-valine promotes the translation and secretion of interferon-γ (IFN-γ) by maintaining endoplasmic reticulum homeostasis. IFN-γ activates macrophage phagocytosis and enhances NK cell killing activity, playing a central role in antiviral and antitumor immunity. L-valine deficiency reduces IFN-γ secretion in T cells by 60%, significantly impairing the body’s immune defense capacity.

IV. Maintaining Intestinal Mucosal Immune Barrier Function

The intestine is a critical line of defense in the immune system, and L-valine indirectly regulates mucosal immunity by supporting intestinal epithelial cell renewal and gut microbiota balance:

Promoting intestinal epithelial cell proliferation and repair: L-valine is a key nutrient for intestinal stem cell proliferation. Its metabolite, α-ketoisovalerate, activates the Wnt/β-catenin pathway in intestinal stem cells, accelerating epithelial cell renewal and enhancing the integrity of the intestinal barrier. This process reduces the translocation of gut microbiota metabolites (e.g., lipopolysaccharides) and lowers the risk of systemic inflammation.

Regulating gut microbiota composition: L-valine serves as a nutritional substrate for probiotics (e.g., Lactobacillus, Bifidobacterium), promoting their proliferation while inhibiting the overgrowth of pro-inflammatory bacteria (e.g., Escherichia coli). Optimization of microbiota structure can influence systemic immune status through the "gut-immune axis"; for example, short-chain fatty acids (SCFAs) produced by probiotic metabolism can further enhance Treg cell differentiation, maintaining immune tolerance.

L-valine achieves precise regulation of the immune system through multiple molecular mechanisms, including metabolic remodeling, signaling pathway modulation, cytokine secretion, and intestinal barrier maintenance. Its role combines dual properties of promoting immune defense and suppressing excessive inflammation, providing a theoretical basis for nutritional intervention in immune-related diseases (e.g., infections, autoimmune diseases, tumors).