Sericin is a protein component consisting of approximately 17-18 different amino acids, with a predominance of serine, aspartic acid and glycine. This complex polypeptide forms naturally in silk and for decades has been discarded as industrial waste from silk production processes. Its anti-inflammatory action is exerted through a multifactorial mechanism that involves the suppression of specific inflammatory signaling pathways and the inhibition of production of molecules key to inflammation mediation.
The primary therapeutic value of sericin lies in its capacity to interfere with biological processes that maintain the inflammatory cascade in an active state. Unlike many synthetic anti-inflammatory drugs, sericin's action occurs through recognition and alteration of specific cellular pathways that control the genesis and perpetuation of inflammation. This characteristic makes it particularly interesting from a pharmacological perspective, as it permits selective interference with pathological mechanisms without necessarily completely blocking the organism's physiological defense processes.
Inhibition of NF-κB and MAPK signaling pathways
One of the mechanisms through which sericin exerts its anti-inflammatory effect involves inhibition of the NF-κB signaling pathway (nuclear factor kappa B). This protein is a crucial transcription factor that is normally found in the cytoplasm of cells in an inactive state, bound to inhibitory proteins. When the cell receives inflammatory signals, particularly from pathogens or inflammation mediators such as lipopolysaccharide (LPS), the NF-κB complex dissociates from its inhibitors and translocates to the nucleus, where it activates transcription of pro-inflammatory genes.
Scientific research has demonstrated that sericin is capable of preventing this activation of the NF-κB complex, maintaining the transcription factor in an inactive state in the cytoplasm. In specific studies, when macrophage cells (the RAW 264.7 cell line) were exposed to LPS in the presence of sericin, a significant reduction in nuclear activation of NF-κB was observed. This effect translates into reduced expression of genes encoding pro-inflammatory cytokines.
At the same time, sericin also influences the MAPK pathway (mitogen-activated protein kinase), another cellular signaling pathway implicated in inflammation regulation. MAPK constitute a family of protein kinases that transmit signals from the cytoplasm to the nucleus in response to inflammatory stimuli and cell growth. Inhibition of these pathways by sericin contributes to further reducing the translation of pro-inflammatory signals within the cell, creating a synergistic effect with NF-κB inhibition.
Suppression of COX-2 and inhibition of nitric oxide production
Cyclooxygenase-2 (COX-2) is a fundamental enzyme in the mediation of inflammation and pain. When inflammation is triggered, COX-2 levels increase significantly in cells, leading to production of prostaglandins, signal molecules that amplify the inflammatory response and associated pain. Studies have documented that sericin is capable of repressing COX-2 gene expression in a dose-dependent manner, with significant reduction already at concentrations of 2.5-10 mg/mL. This ability to modulate COX-2 activity represents one of the most important mechanisms of sericin's anti-inflammatory action.
Concurrently, sericin also acts by inhibiting inducible nitric oxide synthase (iNOS). Nitric oxide produced by iNOS plays a crucial role in inflammation, as it participates in regulating immune response and inflammatory processes. Excessive nitric oxide production is associated with numerous chronic inflammatory pathologies. Sericin intervenes in blocking transcription of the iNOS gene, thereby reducing nitric oxide production at the cellular level. This dual mechanism of COX-2 and iNOS inhibition represents a particularly effective therapeutic approach, as the two enzymes operate simultaneously in the inflammatory cascade.
Modulation of pro-inflammatory cytokines: TNF-α, IL-6 and IL-1β
Pro-inflammatory cytokines constitute the central communication system of inflammation. Among these, tumor necrosis factor alpha (TNF-α) represents one of the key molecules that orchestrate the systemic inflammatory response. When released by immune cells such as macrophages, TNF-α circulates through the body via bloodstream and binds to specific cellular receptors, amplifying the inflammatory signal. Studies have shown that sericin is capable of significantly reducing the production and secretion of TNF-α by stimulated monocytes and macrophages.
Interleukin-6 (IL-6) operates in a manner complementary to TNF-α, acting as an inflammation mediator at both local and systemic levels. Elevated IL-6 concentrations are associated with chronic inflammatory conditions such as rheumatoid arthritis, inflammatory bowel diseases and psoriasis. Specific research has documented that sericin, when taken orally, significantly reduces circulating IL-6 levels in blood serum. This effect suggests that sericin does not act exclusively at the local level, but is capable of modulating the systemic inflammatory cascade.
Interleukin-1 beta (IL-1β) represents another crucial cytokine in the early phase of inflammation. Produced mainly by macrophages and epithelial cells in response to inflammatory stimuli, IL-1β activates endothelial cells, promotes infiltration of immune cells into tissues and promotes production of other cytokines. In vitro studies on cultures of alveolar macrophages have demonstrated that addition of sericin to culture medium reduces IL-1β production in a dose-dependent manner. These results have been confirmed also in in vivo models, where local application of creams based on 8% sericin to wounds determined a significant decrease in IL-1β in affected tissues.
Interleukin-18 and control of the extended inflammatory cascade
Beyond classically known cytokines, sericin shows inhibitory activity also against interleukin-18 (IL-18), a cytokine that amplifies inflammation through mechanisms closely related to IL-1β. IL-18 promotes production of interferon-gamma (IFN-γ) and amplifies the innate inflammatory response. Sericin's capacity to reduce IL-18 levels acts as an additional level of control of the inflammatory cascade, preventing signal amplification through this secondary pathway.
Modulation of the Th1/Th2 profile: sericin as an immunomodulator
A fascinating aspect of sericin's action consists in its capacity to modulate the balance between Th1-type (T helper 1 cells) and Th2-type (T helper 2 cells) immune response. This balance is fundamental for maintaining immune homeostasis. Studies on macrophages treated with low molecular weight sericin (less than 10 kDa) revealed selective upregulation of specific cytokines, in particular CXCL9, IL12A, BMP7 and IL10, with consequent development of a balanced Th1/Th2 profile. This does not simply mean indiscriminate suppression of inflammation, which would be counterproductive from an immune defense standpoint, but rather a rebalancing of the response toward a state of homeostasis.
Increase in interleukin-10 and the protective role of anti-inflammatory cytokines
Parallel to the reduction of pro-inflammatory cytokines, sericin promotes an increase in interleukin-10 (IL-10) levels, a strongly anti-inflammatory and immunoregulatory cytokine. IL-10 operates as a natural brake on the immune system, inhibiting production of pro-inflammatory cytokines by macrophages and dendritic cells. The effect of sericin in increasing IL-10 has been documented in both in vitro and in vivo studies. In particular, when sericin is taken orally, IL-10 levels in blood serum increase significantly, creating a biological environment more favorable to inflammation control. This increase in IL-10 is not due to direct stimulation of producing cells, but rather to restoration of physiological balance among different types of cytokines.
The role of sericin in macrophage polarization
Macrophages represent the so-called "sentinels" of the innate immune system and are capable of adopting two different functional states, termed M1 (pro-inflammatory) and M2 (anti-inflammatory). M1 macrophages produce high quantities of pro-inflammatory cytokines such as TNF-α and IL-6, while M2 macrophages produce anti-inflammatory cytokines and promote tissue repair processes. Research has documented that sericin promotes polarization of macrophages toward the M2 phenotype, simultaneously reducing the proportion of M1 macrophages. This change in the macrophage population contributes significantly to the overall anti-inflammatory effect of sericin.
Fluorescence microscopy studies have shown a clear alteration of macrophage surface markers when exposed to sericin, with reduction of iNOS (M1 marker) and increase of Arg-1 (M2 marker). This effect was further confirmed by flow cytometry, which revealed a shift in the macrophage population from the inflammatory phenotype to the repair phenotype. Such polarization is particularly relevant in the context of wound healing, where M2 macrophages play a central role in controlling inflammation and promoting tissue repair.
Effect of route of administration on anti-inflammatory action
An important aspect that emerged from scientific research concerns the mode of sericin administration. Oral ingestion of sericin produces a consistent anti-inflammatory response profile, with reduction of central pro-inflammatory cytokines and increase of IL-10. However, intravenous injection produces apparently paradoxical effects, with initial increase of TNF-α, IL-6 and IL-12 and transient reduction of anti-inflammatory factors. This suggests that sericin, when taken orally, undergoes processing in the gastrointestinal tract that modulates its biological activity, while direct injection into the bloodstream can temporarily activate the innate response. Therefore, for anti-inflammatory applications, the oral route proves to be the most appropriate, particularly useful in conditions such as ulcerative colitis and other inflammatory bowel diseases.
Gamma-irradiated sericin and mechanisms of immune enhancement
Specific treatments of sericin, such as gamma irradiation at 5 kGy, have demonstrated interesting immunopotentiating properties. Irradiated sericin (I-sericin) significantly increases proliferation of immune cells and activation of natural killer (NK) cells, concurrently with a more pronounced reduction of lipopolysaccharide-induced inflammation. In studies on mice fed I-sericin for four weeks and subsequently treated with LPS, a significantly increased proliferation of lymphocytes was observed and a decrease in secretion of inflammatory cytokines. This suggests that specific treatments of sericin can enhance its immunomodulatory effects, even though the exact mechanisms of how irradiation modifies protein structure remain partially unclear.
Application of sericin in specific pathological conditions
The capacity of sericin to modulate pro-inflammatory cytokines makes it particularly promising in treating conditions characterized by altered inflammatory profile. In psoriasis, an autoimmune skin disease, studies on peripheral blood mononuclear cells from psoriatic patients have demonstrated that sericin alone and in combination with other phytoconstituents significantly reduces gene expression and production of TNF-α, IL-6, IL-23 and IL-12p40. These results suggest that sericin could represent a complementary approach in treating inflammatory dermatological diseases.
In the context of wound healing, sericin's capacity to modulate the inflammatory profile translates into acceleration of the repair process. When incorporated into tissue scaffolds together with supernatants from mesenchymal stem cells stimulated by pro-inflammatory cytokines, sericin promotes macrophage polarization toward the M2 phenotype, promotes angiogenesis, stimulates re-epithelialization and increases collagen deposition. All these effects contribute to faster and more effective wound healing in animal models.
Optimal concentration and dose-response curve
An important element for clinical application of sericin concerns identification of optimal concentration. Studies indicate that anti-inflammatory effect is generally dose-dependent, but with a well-defined therapeutic window. Concentrations in the range of 0.1-10 mg/mL show the most significant effects in cellular models, while excessive concentrations (>1 mg/mL in some applications) may determine a reduction in cell viability. This non-linear dose-response curve underscores the importance of standardized formulations and research of optimal dosage for specific clinical applications.
Considerations on biocompatibility and potential safety mechanisms
A crucial therapeutic advantage of sericin consists in its high biocompatibility and lack of intrinsic immunogenicity. While previous studies suggested a potential capacity of sericin to elicit an immune response, more recent research has clarified that this reactivity occurs only when sericin remains physically associated with silk fibroin, its natural protein complex. Purified sericin does not induce significant immunogenic effects, making it suitable for biomedical applications. This lack of immunogenicity represents a significant advantage compared to many synthetic anti-inflammatory drugs, which can generate adverse immune responses in a fraction of patients.
Biodegradability of sericin is another favorable attribute. It does not remain as a foreign body in the body, but is progressively degraded by the endogenous proteolytic system. This characteristic is particularly important when sericin is used in scaffolds for regenerative medicine, where controlled degradation is essential to permit replacement of the protein structure with newly formed tissue.
Perspectives and clinical potential
Research on anti-inflammatory sericin is in a phase of transition between preclinical studies and clinical applications. Increasingly precise molecular characterization of its mechanisms of action, combined with identification of predictive animal models, drives studies toward diverse inflammatory pathologies. The most interesting potentials concern inflammatory bowel diseases, rheumatoid arthritis, inflammatory dermatitis and improvement of chronic wound healing processes. Moreover, sericin's capacity to modulate the Th1/Th2 balance could prove particularly useful in conditions characterized by dysregulation of adaptive immune system.
