By Cocer Peptides 
1 month ago
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Basic Information about KPV
KPV is a tripeptide with significant anti-inflammatory properties, which enable it to play a role in many fields.
Figure 1 The Therapeutic Effects of HA-KPV-NPs against UC Oral administration of HA-KPV-NPs embedded in hydrogel (chitosan/alginate) confers combined therapeutic effects against UC by accelerating mucosa healing and alleviating inflammation.
Anti-inflammatory Mechanism of KPV
1. Regulation of Cell Signaling Pathways
NF-κB Signaling Pathway: NF-κB is a key transcription factor playing a central role in inflammatory responses. When cells are exposed to inflammatory stimuli, NF-κB translocates from the cytoplasm to the nucleus, initiating the transcription of pro-inflammatory cytokine genes. KPV can inhibit the activation of NF-κB. In human intestinal epithelial cells and human T cells, cells were stimulated with pro-inflammatory cytokines, and KPV was added simultaneously. Using methods such as NF-κB luciferase gene reporter assays, protein immunoblotting, real-time reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay (ELISA), it was found that KPV at nanomolar concentrations can inhibit NF-κB activation, thereby reducing the secretion of pro-inflammatory cytokines. This mechanism is crucial in the regulation of intestinal inflammation, as excessive activation of NF-κB in intestinal epithelial cells and immune cells is a key feature of inflammatory bowel disease (IBD) and other intestinal inflammatory conditions.
MAP kinase signaling pathway: The mitogen-activated protein kinase (MAPK) signaling pathway is another important regulatory pathway in inflammatory responses, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. These kinases are activated when cells are exposed to inflammatory stimuli, leading to the phosphorylation of downstream transcription factors and promoting the expression of inflammation-related genes. KPV can also inhibit the MAP kinase inflammatory signaling pathway. When cells are exposed to inflammatory stimuli, KPV can block MAPK activation, reducing its phosphorylation of downstream transcription factors, thereby decreasing the production of pro-inflammatory cytokines. In an inflammatory state, activation of p38 MAPK leads to increased expression of pro-inflammatory cytokines such as TNF-α and IL-6, while KPV can inhibit p38 MAPK activity, reducing the secretion of these cytokines and thereby alleviating the inflammatory response.
2. Cell transporter-mediated effects
PepT1 transporter: PepT1 is a di/tripeptide transporter typically expressed in the small intestine but induced in the colon during IBD. The anti-inflammatory effects of KPV are partially mediated by PepT1. In uptake experiments, cold KPV was used as a competitive inhibitor for hPepT1 as a radioactive labeled substrate, or [⊃3;H]KPV was used to determine the kinetic characteristics of KPV uptake. KPV enters immune cells and intestinal epithelial cells via hPepT1. This indicates that PepT1, as a transporter, facilitates KPV entry into cells to exert its anti-inflammatory effects. When PepT1 function is inhibited, the amount of KPV entering cells decreases, and its anti-inflammatory effects are correspondingly weakened. In cell models with knockdown of PepT1 expression, even when administered at the same concentration, KPV exhibits significantly reduced inhibitory effects on NF-κB activation and reduced secretion of pro-inflammatory cytokines compared to cells with normal PepT1 expression, further confirming the crucial mediating role of PepT1 in the anti-inflammatory mechanism of KPV.
3. Regulation of inflammatory cytokines
Inhibition of pro-inflammatory cytokines: KPV can significantly inhibit the production and release of multiple pro-inflammatory cytokines. TNF-α is a key cytokine in inflammatory responses, capable of activating immune cells, inducing the production of other pro-inflammatory cytokines, and causing tissue damage. In various inflammatory models, the expression levels of TNF-α were significantly reduced after KPV treatment. For example, in a sodium sulfate-induced mouse colitis model, treatment with KPV resulted in a significant reduction in the mRNA expression of TNF-α in colon tissue, as detected by real-time RT-PCR, and a significant decrease in the protein content of TNF-α in serum, as detected by ELISA. IL-1β, IL-6, and other pro-inflammatory cytokines were also inhibited by KPV. IL-1β can trigger an inflammatory cascade reaction, promoting the release of other inflammatory mediators. KPV can reduce its expression and secretion in inflammatory tissues, thereby alleviating the intensity of the inflammatory response.
Promotion of anti-inflammatory cytokines: In addition to inhibiting pro-inflammatory cytokines, KPV can also promote the expression of anti-inflammatory cytokines. Interleukin-10 (IL-10) is an important anti-inflammatory cytokine that can inhibit the activation of immune cells and reduce the production of pro-inflammatory cytokines.
4. Regulation of immune cells
Regulation of T cell function: T cells play a crucial role in immune responses and inflammation regulation. Under inflammatory conditions, T cells are activated and secrete pro-inflammatory cytokines. Studies have shown that KPV can regulate T cell function. In experiments with the human T cell line Jurkat, when Jurkat cells were stimulated with pro-inflammatory cytokines, the addition of KPV inhibited T cell activation and reduced the secretion of pro-inflammatory cytokines such as IFN-γ. This may be achieved by inhibiting the NF-κB and MAPK signaling pathways within T cells. Additionally, in some animal models, such as the CD45RB(hi) colonic inflammation model, KPV treatment can regulate T cell infiltration and function in the intestine, reduce inflammation-related T cell subsets such as Th1 and Th17 cells, and increase the proportion of regulatory T cells, thereby alleviating intestinal inflammation.
Modulation of macrophage function: Macrophages are important immune cells in the inflammatory response and can be classified into classically activated M1 macrophages and alternatively activated M2 macrophages based on their activation state. M1 macrophages secrete large amounts of pro-inflammatory cytokines, while M2 macrophages possess anti-inflammatory and tissue repair functions. KPV can regulate macrophage polarization. In vitro experiments showed that when macrophages were stimulated with lipopolysaccharide (LPS) to polarize toward the M1 type, co-administration of KPV inhibited macrophage polarization toward the M1 type, reduced the expression of M1 macrophage markers, while promoting their polarization toward the M2 type, increasing the expression of M2 macrophage markers (such as arginase-1 Arg-1). In in vivo inflammatory models, such as DSS-induced colitis in mice, treatment with KPV resulted in more macrophages in the colon tissue polarizing toward the M2 type, thereby alleviating inflammatory responses and promoting tissue repair.
5. Protective effects on intestinal epithelial cells
Enhancing epithelial barrier function: The physical barrier formed by intestinal epithelial cells serves as the first line of defense against pathogen and harmful substance invasion. In inflammatory states, impaired intestinal epithelial barrier function leads to bacterial translocation and endotoxin leakage, further exacerbating inflammatory responses. KPV can enhance the barrier function of intestinal epithelial cells. In vitro cell experiments, where intestinal epithelial cell lines were treated with pro-inflammatory cytokines to simulate an inflammatory environment, resulted in reduced expression of tight junction proteins (such as ZO-1 and occludin) and impaired barrier function. However, the addition of KPV maintains the expression of tight junction proteins, enhances intercellular connections, and restores the barrier function of intestinal epithelial cells. In DSS-induced colitis mice treated with KPV, immunohistochemistry and Western blot analysis revealed increased expression of tight junction proteins in colon tissue and reduced intestinal permeability, indicating that KPV protects the intestinal epithelial barrier in vivo, reduces the invasion of harmful substances, and alleviates inflammatory responses.
Promoting epithelial cell proliferation and repair: Inflammation can cause damage and death of intestinal epithelial cells, impairing normal intestinal function. KPV has the ability to promote the proliferation and repair of intestinal epithelial cells. In vitro cell culture experiments showed that treating damaged intestinal epithelial cells with KPV enhanced cell proliferation, as detected by the Cell Counting Kit (CCK-8). Additionally, immunofluorescence analysis revealed increased expression of proliferating cell nuclear antigen (PCNA), indicating that cells were in an active proliferative state. In a TNBS-induced ulcerative colitis rat model, after treatment with KPV/SH-PGA hydrogel, histological observations revealed that damage to colonic epithelial cells was repaired, and crypt structures gradually returned to normal. This may be related to KPV's promotion of epithelial cell proliferation and repair, which helps alleviate inflammation and promote intestinal tissue recovery.
Figure 2 KPV is therapeutic in DSS colitis.
6. Antioxidant effects
Regulation of oxidative stress-related markers: Inflammation is often accompanied by oxidative stress reactions, with increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to oxidative damage to cells and tissues. KPV exhibits antioxidant effects and can regulate oxidative stress-related markers. In some inflammatory models, such as the cotton ball-induced mouse granuloma model and the egg white-induced rat dorsal air sac synovitis model, elevated levels of malondialdehyde (MDA) and reduced superoxide dismutase (SOD) activity were detected in inflammatory tissues. Following KPV treatment, MDA levels significantly decreased, and SOD activity increased. MDA is a product of lipid peroxidation, and its reduced levels indicate diminished lipid peroxidation damage to cells; SOD is an important antioxidant enzyme, and its increased activity signifies enhanced ability to scavenge free radicals. KPV can mitigate oxidative damage in inflammatory tissues by regulating oxidative stress levels, thereby exerting anti-inflammatory effects.
7. Other Potential Mechanisms
Relationship with the melanocortin receptor: KPV is a tripeptide derived from α-MSH. Although its anti-inflammatory effects are partially independent of MC1R signaling, they may be associated with MC1R in certain contexts. In animals expressing MC1Re/e, KPV treatment following DSS-induced colitis still exerted significant anti-inflammatory effects, rescuing all animals in the treatment group from death during DSS-induced colitis, indicating that KPV's anti-inflammatory effects are at least partially independent of MC1R signaling. In animals with normal MC1R expression, KPV may enhance anti-inflammatory effects by interacting with MC1R or regulating its downstream signaling pathways.
Anti-inflammatory Effects of KPV
1. Role in intestinal inflammation models
DSS-induced colitis model: In the DSS-induced mouse colitis model, KPV demonstrated significant anti-inflammatory effects. In terms of weight changes, mice treated with KPV recovered their weight earlier and to a greater extent compared to untreated mice. Histological observations revealed a marked reduction in inflammatory infiltration in the colon tissue of KPV-treated mice, further confirmed by a significant decrease in myeloperoxidase (MPO) activity. MPO is an enzyme present in neutrophils, and its activity levels reflect the extent of inflammatory cell infiltration in tissues. The reduction in MPO activity following KPV treatment indicates decreased neutrophil infiltration in colon tissue and alleviated inflammatory responses. By detecting the mRNA expression of pro-inflammatory cytokines in colonic tissue, such as TNF-α and IL-1β, it was found that KPV treatment significantly reduced the expression levels of these pro-inflammatory cytokines. KPV alleviated DSS-induced colitis symptoms from multiple aspects, including reducing inflammatory cell infiltration, lowering inflammatory factor expression, and promoting weight recovery.
CD45RB(hi) colonic inflammation model: In the CD45RB(hi) colonic inflammation model, KPV also demonstrated good anti-inflammatory effects. This model was induced by transferring T cells highly expressing CD45RB into immunodeficient mice. Following KPV treatment, the mice exhibited improved inflammatory symptoms, gradual weight recovery, and histological examination revealed reduced intestinal inflammatory changes. The KPV-treated group showed decreased inflammatory cell infiltration and reduced crypt structural damage in intestinal tissues, indicating that KPV effectively alleviates CD45RB(hi)-induced intestinal inflammation and restores normal intestinal tissue structure and function.
TNBS-induced ulcerative colitis model: In the TNBS-induced ulcerative colitis rat model, KPV also demonstrated significant therapeutic effects. After administering KPV/SH-PGA hydrogel rectally to rats, colitis symptoms improved markedly. The degree of weight loss in rats was alleviated, and the disease activity index (DAI) score decreased. The DAI score comprehensively considers indicators such as changes in rat body weight, fecal characteristics, and hematochesia. Its reduction indicates that the KPV/SH-PGA hydrogel can effectively alleviate the severity of TNBS-induced ulcerative colitis. KPV/SH-PGA hydrogel treatment also prevents colon shortening in rats, reduced colonic myeloperoxidase levels, and restored colonic morphological structure, including the epithelial barrier, crypts, and intact goblet cells. The expression of pro-inflammatory cytokines, TNF-α and IL-6, in colonic tissue was also significantly reduced, further demonstrating the anti-inflammatory effect of KPV in the TNBS-induced ulcerative colitis model.
Conclusion
KPV, as a tripeptide with anti-inflammatory properties, demonstrates promising effects in the prevention and treatment of intestinal inflammation and various other inflammation-related diseases. Its anti-inflammatory mechanisms involve multiple aspects, including regulation of cellular signaling pathways, antioxidant stress, and modulation of apoptosis and autophagy.
Sources
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