The Cytokine TGF-ß Induces Interleukin-31 Expression from Dermal Dendritic Cells to Activate Sensory Neurons and Stimulate Wound Itching.

Cutaneous wound healing is associated with the unpleasant sensation of itching. Here we investigated the mechanisms underlying this type of itch, focusing on the contribution of soluble factors released during healing. We found high amounts of interleukin 31 (IL-31) in skin wound tissue during the peak of itch responses. Il31-/- mice lacked wound-induced itch responses. IL-31 was released by dermal conventional type 2 dendritic cells (cDC2s) recruited to wounds and increased itch sensory neuron sensitivity. Transfer of cDC2s isolated from late-stage wounds into healthy skin was sufficient to induce itching in a manner dependent on IL-31 expression. Addition of the cytokine TGF-ß1, which promotes wound healing, to dermal DCs in vitro was sufficient to induce Il31 expression, and Tgfbr1f/f CD11c-Cre mice exhibited reduced scratching and decreased Il31 expression in wounds in vivo. Thus, cDC2s promote itching during skin would healing via a TGF-ß-IL-31 axis with implications for treatment of wound itching.

Characterisation of the pruritus responses and pruritic behaviours in an interleukin 31-induced canine model of pruritus.

BACKGROUND: Intravenous administration of interleukin (IL)-31 in healthy dogs has been used as a model to assess antipruritic drugs. However, there is no known in-depth characterisation of pruritic behaviours, and the repeatability of the IL-31-induced pruritus in the individual dogs is currently unknown. OBJECTIVES: To evaluate the immediate/delayed pruritus responses and the pruritic behaviours observed in the IL-31-induced pruritic model in healthy dogs after repeated IL-31 injections. ANIMALS: Fifteen healthy laboratory beagles. METHODS: All dogs were video-recorded for 270 min after two intravenous recombinant IL-31 injections (1.75 µg/kg) and vehicle (phosphate-buffered saline, control) injections, respectively; interventions were randomised and performed with a 2 week wash-out period. Two blinded investigators reviewed the pruritic behaviours of all video recordings. RESULTS: Both canine IL-31 (IL-31_01, IL-31_02) injections significantly increased pruritic seconds and categorical minutes ('YES'/'NO' behaviour per discrete 1 min interval) in healthy dogs compared with both vehicle groups (Vehicle_01, Vehicle_02). The second intravenous canine IL-31 (IL-31_02) administered 14 days after the first IL-31 injection induced a significant increase in pruritic seconds (p = 0.021) and not pruritic categorical minutes (p = 0.231). An increase in pruritic seconds was observed in both IL-31 groups in the first 30 min post-administration, while there was no significant difference between IL-31 and vehicle groups. CONCLUSIONS AND CLINICAL RELEVANCE: In conclusion, intravenous IL-31 reproducibly induces itch responses in dogs. Future evaluations of the canine IL-31 pruritic model should assess total pruritic behaviours in seconds rather than using a biased 'YES/NO' behaviour per 1 min scoring system.

A systematic review of interleukin-31 inhibitors in the treatment of prurigo nodularis.

BACKGROUND: Prurigo nodularis (PN) is a neuroimmunological skin disease. Severe itching is the most challenging symptom which affects patients' quality of life. T helper 2-derived cytokines, such as interleukin-31 and oncostatin M (OSM), play a crucial role in PN pathogenesis. Nemolizumab and vixarelimab are two biologics acting as IL-31 inhibitors. Vixarelimab also suppresses the OSM activity. This systematic review evaluates the efficacy and safety of nemolizumab and vixarelimab in PN management. METHODS: A systematic search was conducted in PubMed/Medline, Ovid Embase, and Web of Science up to September 17th, 2023. Clinical trials and cohort studies published in English were included. RESULTS: Among a total of 96 relevant records, five were included. The results of four studies with 452 patients using nemolizumab showed that a significantly higher percentage of patients treated with nemolizumab demonstrated a reduction in peak pruritus numerical rating scale (PP-NRS) and investigator's global assessment along with improved sleep disturbance (SD) and quality of life than the placebo group. Moreover, one study administered vixarelimab to 49 PN patients, and their finding illustrated a higher rate of subjects who received vixarelimab experienced ≥ 4-point diminution in worst itch NRS, visual analog scale, healing of representative lesions, and SD quality compared to the placebo group. CONCLUSIONS: IL-31 inhibitors suggest distinct advantages in improving pruritus, sleep quality, and overall quality of life in subjects with moderate-to-severe PN. Further clinical studies are recommended to compare the effectiveness of these biologics to other therapeutic choices.

Levels of serum inflammatory cytokines and their correlations with disease severity in patients with chronic spontaneous urticaria.

Introduction: Inflammation is crucial in the pathogenesis of chronic spontaneous urticaria (CSU). Investigating the correlation between levels of serum inflammatory cytokines (SICs) and the severity of CSU is of great significance for understanding the disease mechanism and finding effective treatment strategies. Aim: In this context, this work was developed. Material and methods: This work involved a researchy group (Res group) of 114 patients with CSU and a control group (Ctrl group) of 100 healthy individuals. SICs including leukotriene B4 (LTB4), leukotriene C4 (LTC4), interleukin (IL) 4 (IL-4), IL-17, IL-31, and tumor necrosis factor-γ (TNF-γ), of patients in different groups were measured and compared. Furthermore, the correlations between each SIC and pruritus severity, duration of pruritus, urticaria activity, and quality of life (QOL) were compared among the patients in different groups. Results: The Res group exhibited higher levels of LTB4, LTC4, IL-4, IL-17, and IL-31 but lower levels of TNF-γ. Great differences (p < 0.05) were found in IL-4, IL-17, and IL-31 among the patients with different pruritus severity, and positive correlations were observed between IL-17 and IL-31 levels and urticaria activity in the patients (p < 0.05). Additionally, levels of IL-4 and IL-31 exhibited a positive association to QOL scores in the patients, with obvious differences (p < 0.05). Conclusions: IL-4, IL-17, and IL-31 showed the strongest correlation with the severity of CSU, which may be attributed to their involvement in immune, inflammatory, and pruritic reactions, exacerbating the disease condition.

Interleukin-31 in serum and cerebrospinal fluid of dogs with syringomyelia.

BACKGROUND: Syringomyelia is a spinal cord cavity containing cerebrospinal fluid (CSF)-like fluid. If syringomyelia asymmetrically involves the dorsal horn grey matter of the spinal cord, affected dogs show increased signs of dysesthesia and neuropathic pain, like increased itching behaviour. In the dorsal horn, amongst others, receptors for Interleukin-31 (IL-31) can be found. IL-31 is one of the main cytokines involved in the pathogenesis of pruritus in atopic dermatitis in different species. This study investigates suspected elevated levels of IL-31 in serum and CSF of dogs showing signs of pain or increased itching behaviour related to syringomyelia. The IL-31 were measured in archived samples (52 serum and 35 CSF samples) of dogs with syringomyelia (n = 48), atopic dermatitis (n = 3) and of healthy control dogs (n = 11) using a competitive canine IL-31 ELISA. RESULTS: Mean serum IL-31 level in dogs with syringomyelia was 150.1 pg/ml (n = 39), in dogs with atopic dermatitis 228.3 pg/ml (n = 3) and in healthy dogs 80.7 pg/ml (n = 10). Mean CSF IL-31 value was 146.3 pg/ml (n = 27) in dogs with syringomyelia and 186.2 pg/ml (n = 8) in healthy dogs. Individual patients with syringomyelia (especially dogs with otitis media or otitis media and interna or intervertebral disc herniation) showed high IL-31 levels in serum and CSF samples, but the difference was not statistically significant. IL-31 serum and CSF levels did not differ significantly in dogs with syringomyelia with or without itching behaviour and with or without signs of pain. CONCLUSION: Based on this study, increased IL-31 levels seem not to be correlated with itching behaviour or signs of pain in dogs with syringomyelia, but might be caused by other underlying diseases.

Expression, purification, and biological characterization of recombinant human interleukin-31 protein.

Interleukin-31 (IL-31), belonging to the IL-6 cytokine family, is involved in skin inflammation and pruritus, as well as some tumors' progression. Here, we reported the expression and purification of recombinant human IL-31 (rhIL-31) using a prokaryotic system. This recombinant protein was expressed in the form of inclusion bodies, refolded and purified by size-exclusion chromatography. Circular dichroism analysis revealed that the secondary structure of rhIL-31 was mainly composed of alpha-helix, which is in consistence with the 3D model structure built by AlphaFold server. In vitro studies showed that rhIL-31 exhibited a good binding ability to the recombinant hIL-31 receptor alpha fused with human Fc fragment (rhIL-31RA-hFc) with EC50 value of 16.36 µg/mL in ELISA assay. Meanwhile, flow cytometry demonstrated that rhIL-31 was able to bind to hIL-31RA or hOSMRß expressed on the cell surface, independently. Furthermore, rhIL-31 could induce the phosphorylation of STAT3 in A549 cells. In conclusion, the prepared rhIL-31 in this study possesses the binding ability to its receptors, and can activate the signal pathway of JAK/STAT. Thus, it can be applied in further studies, including investigation of hIL-31-related diseases, structural analysis, and development of therapeutic drugs, and monoclonal antibodies targeting hIL-31.

Interleukin-31 Receptor A Expression in the Dorsal Root Ganglion of Mice with Atopic Dermatitis.

Atopic dermatitis (AD) is a common skin disease caused by genetic and environmental factors. However, the mechanisms underlying AD development remain unclear. In this study, we examined the genetic factors contributing to the onset of itch-associated scratching in different strains of mice. Interleukin-31 (IL-31) induces severe scratching and dermatitis in mice. However, the site of action of IL-31 remains unclear. Cutaneous IL-31 and IL-31 receptor A (IL-31RA) mRNAs in the dorsal root ganglion (DRG) are expressed exclusively in the AD model, i.e., NC/Nga mice. Here we evaluated the effects of repeated administration of IL-31 on the scratching behavior in NC/Nga, BALB/c, and C57BL/6 mice. The results showed that repeated administration of IL-31 significantly increased itch-associated scratching (LLS) behavior in the three strains of mice. One hour after an intravenous IL-31 injection, BALB/c mice showed alloknesis-like behavior. Mite infestation and IL-31 administration triggered itchy skin, increased LLS counts and DRG neuronal IL-31RA expression, and eventually caused dermatitis. The dermatitis severity and LLS counts induced by mite infestation and IL-31 administration were in the order NC/Nga > BALB/c > C57BL/6. In conclusion, neuronal IL-31RA expression in the DRG was the most important genetic factor affecting the severity of LLS and dermatitis in mice.

Association of Periodontitis and Atopic Dermatitis with the Levels of IL-13, IL-31, and TSLP in the Gingival Crevicular Fluid.

Emerging epidemiological evidence links atopic dermatitis (AD) and periodontitis, although the mechanisms remain unclear. Th2-derived cytokines are key in the development of both diseases, and different gingival crevicular fluid (GCF) profiles among healthy and diseased subjects have been previously reported. This case-control study examined the GCF levels of interleukins (IL)-13, IL-31, and thymic stromal lymphopoietin (TSLP) in 29 subjects with moderate-to-severe AD and 33 controls. All subjects underwent comprehensive clinical and oral evaluations, followed by GCF collection. GCF levels of IL-13, IL-31, and TSLP were assessed using a multiplex-bead immunoassay. Demographic and periodontal parameters were similar among groups (p > 0.05). The GCF levels of IL-31 and TSLP were higher in AD subjects compared to controls (p < 0.05), whereas no significant differences in the GCF levels of IL-13 were noticed (p = 0.377). Moderate-to-severe AD was positively associated with the GCF levels of IL-31 and TSLP, whereas severe periodontitis was negatively associated with IL-31 (p < 0.05). The GCF levels of IL-13 showed no significant associations with either condition (p = 0.689). There was no significant interaction between AD and periodontitis for IL-31 (p < 0.869). These results suggest that AD and periodontitis independently influence the GCF levels of IL-31 in opposing ways, whereas AD alone influences the levels of TSLP.

Experimental Study: Interleukin-31 Augments Morphine-Induced Antinociceptive Activity and Suppress Tolerance Development in Mice.

Morphine-induced antinociception is partially reduced in interleukin-31 (IL-31) receptor A (IL-31RA)-deficient mice, indicating that IL-31RA is crucial for morphine-induced peripheral antinociception. Herein, we examined the combined effects of IL-31 and morphine on the antinociceptive activity and itch-associated scratching behavior (LLS) in mice and elucidated the regulatory mechanisms. A hot-plate test was used to assess antinociception. LLS was automatically detected and recorded via a computer. IL-31RA mRNA expression was assessed using real-time polymerase chain reaction. Repeated pre-treatment with IL-31 resulted in significant antinociceptive activity. Repeated administration of morphine decreased the morphine-induced antinociceptive activity, LLS counts, and regular dose and inhibited IL-31-induced LLS. These results suggested that the repeated administration of morphine depleted inter-neuronal IL-31RA levels, preventing morphine-induced antinociception. Therefore, IL-31 may be helpful as an adjunct analgesic to morphine. To explore the benefits of IL-31, its influence on morphine-induced antinociceptive tolerance in mice was examined. An IL-31 and morphine combination increased the analgesic action, which increased the expression of DRG neuronal IL-31RA, elucidating the site of peripheral antinociception of morphine. This site may induce exocytosis of IL-31RA in the sensory nervous system. Collectively, the suppressive effect of IL-31 on morphine-induced antinociceptive tolerance may result from IL-31RA supplementation in sensory nerves.

Analyzing the Antinociceptive Effect of Interleukin-31 in Mice.

The theory that an itch inhibits pain has been refuted; however, previous research did not investigate this theory for an interleukin-31 (IL-31)-induced itch. Previously, we have found that morphine-induced antinociception was partially reduced in IL-31 receptor A (IL-31RA)-deficient (IL-31RAKI) mice, indicating that IL-31RA may play an important role in morphine-induced peripheral antinociception. In the present study, we evaluated the effect of IL-31-induced analgesia on a 2,4,6-trinitrochlorobenzene (TNCB)-sensitized mice using a hot-plate test. This test evaluated the antinociceptive activity of morphine and non-steroidal anti-inflammatory drugs (NSAIDs). Repeated pretreatment with IL-31 showed significant antinociceptive action. Furthermore, its combination with morphine, but not with NSAIDs, increased the analgesic action. In contrast, treatment with TNCB and capsaicin decreased antinociception. Moreover, TNCB increased IL-31RA expression in the dorsal root ganglia at 24 h, whereas capsaicin inhibited it. The comparative action of several analgesics on TNCB or capsaicin was evaluated using a hot-plate test, which revealed that the antinociceptive activity was decreased or disappeared in response to capsaicin-induced pain in IL-31RAKI mice. These results indicate that the analgesic action of IL-31 involves the peripheral nervous system, which affects sensory nerves. These results provide a basis for developing novel analgesics using this mechanism.

Overexpression of helper T cell type 2-related molecules in the skin of patients with eosinophilic dermatosis of hematologic malignancy.

BACKGROUND: Eosinophilic dermatosis of hematologic malignancy (EDHM) is a rare dermatosis associated with blood tumors. OBJECTIVE: To characterize the expression of T-cell and B-cell markers and pruritogenic mediators in EDHM skin. METHODS: Immunohistochemical and immunofluorescence analysis were performed in 12 skin samples of EDHM, 11 samples of bullous pemphigoid (BP), and 5 samples from healthy controls (HC). Serum levels of interleukin (IL) 4 were analyzed in 11 patients with EDHM, 11 BP patients, and 5 HC by enzyme-linked immunosorbent assay. RESULTS: T-cell markers, including clusters of differentiation (CD) 3, CD4, CD8, and CD5 were significantly overexpressed in EDHM and BP skin compared to HC. A predominance of CD4+ over CD8+ cells and GATA3+ (helper T cell type 2 [Th2] marker) over T-bet+ (Th1 marker) cells were observed. FOXP3 expression was increased but the FOXP3/CD4 ratio was low. B-cell markers were under-represented, without significant differences between the 3 groups. IL-4 and IL-31 were significantly overexpressed in EDHM and BP compared to HC and colocalized with the Th2-associated marker GATA3. Eotaxin-1 was significantly overexpressed in EDHM compared to BP and HC. IL-4 serum concentration was significantly increased in EDHM and BP compared to HC. LIMITATIONS: Small sample size; retrospective design. CONCLUSIONS: Targeting Th2-related molecules, in particular IL-4, holds promise for EDHM management.

IL-31: State of the Art for an Inflammation-Oriented Interleukin.

Interleukin 31 belongs to the IL-6 superfamily, and it is an itch mediator already studied in several diseases, comprising atopic dermatitis, allergic pathologies, and onco-hematological conditions. This research aims to assess the role of this cytokine in the pathogenesis of these conditions and its potential therapeutic role. The research has been conducted on articles, excluding reviews and meta-analysis, both on animals and humans. The results showed that IL-31 plays a crucial role in the pathogenesis of systemic skin manifestations, prognosis, and itch severity. Traditional therapies target this interleukin indirectly, but monoclonal antibodies (Mab) directed against it have shown efficacy and safety profiles comparable with biological drugs that are already available. Future perspectives could include the development of new antibodies against IL-31 both for humans and animals, thus adding a new approach to the therapy, which often has proven to be prolonged and specific for each patient.

Critical Players and Therapeutic Targets in Chronic Itch.

Chronic itch is one of the most prominent clinical characteristics of diverse systematic diseases. It is a devastating sensation in pathological diseases. Despite its importance, there are no FDA-labelled drugs specifically geared toward chronic itch. The associated complex pathogenesis and diverse causes escalate chronic itch to being one of the top challenges in healthcare. Humanized antibodies against IL-13, IL-4, and IL-31 proved effective in treatment of itch-associated atopic dermatitis but remain to be validated in chronic itch. There are still no satisfactory anti-itch therapeutics available toward itch-related neuropeptides including GRP, BNP, SST, CGRP, and SP. The newly identified potential itch targets including OSM, NMB, glutamate, periostin, and Serpin E1 have opened new avenues for therapeutic development. Proof-of-principle studies have been successfully performed on antagonists against these proteins and their receptors in itch treatment in animal models. Their translational interventions in humans need to be evaluated. It is of great importance to summarize and compare the newly emerging knowledge on chronic itch and its pathways to promote the development of novel anti-itch therapeutics. The goal of this review is to analyze the different physiologies and pathophysiologies of itch mediators, whilst assessing their suitability as new targets and discussing future therapeutic development.

Interleukin-31 is overexpressed in skin and serum in cutaneous T-cell lymphomas but does not correlate to pruritus.

Introduction: Cutaneous T-cell lymphomas (CTCL) are malignant lymphoproliferative disorders accompanied by persistent pruritus. Pruritogenic role of interleukin-31 (IL-31) has been studied extensively and was proven in atopic dermatitis (AD), while its role in CTCL is still rather vague. Aim: To investigate IL-31 serum level along with IL-31, IL-31 receptor α (IL-31RA) and oncostatin M receptor ß (OSMR) skin expression in CTCL and compare it to controls: AD and healthy volunteers. Material and methods: The level of IL-31 in serum was measured using ELISA, while IL-31 and receptors' expression in the skin were measured using immunohistochemistry and correlated with the stage of disease and pruritus severity. Results: Expression of IL-31 and IL-31 receptor in serum and skin were significantly higher in CTCL and AD in comparison to healthy controls. No significant correlation between the IL-31 serum level and pruritus severity in CTCL patients was found. There was also no correlation between IL-31/IL-31RA/OSMR expression in the skin and CTCL pruritus, while IL-31 and IL-31RA in CTCL skin negatively correlated with the stage of disease. Conclusions: Our data indicate that IL-31 does not play a crucial role in pruritus in CTCL but it is rather involved in the pathogenesis of the disease. It seems that IL-31 plays an essential role in the pruritus pathomechanism that is unique to AD.

Elevated interleukin 31 serum levels in hemodialysis patients are associated with uremic pruritus.

INTRODUCTION: Uremic pruritus is a multifactorial devastating complication of renal failure, which has a significant negative impact on patients' quality of life including medical, psychological, as well as social aspects. It is also associated with an increased mortality in dialysis patients. METHODS: A cross sectional study evaluating the traditional risk factors for uremic pruritus (UP) - using pruritus grading system (PGS) and visual analogue scale (VAS) - as well as measuring the serum levels of different inflammatory cytokines (ILs 13, 31 and 33) in chronic hemodialysis and healthy controls, in a tertiary referral hospital. RESULTS: 65 hemodialysis (HD) patients and 49 heathy controls were enrolled in the study. The mean age for the HD patients was 43.4 years (SD ± 21.3), and 31.5 years (SD ± 11.1) for the control group. The most common cause for End Stage Renal Disease (ESRD) was diabetes mellitus (DM) 27.7%. The mean PGS score in HD patients was 5.92 (SD ± 2.9); 50% had mild itch, 43.8% moderate itch and 6.2% had severe itch. The mean serum levels for IL-13 was 8674.3 pg/ml (SD ± 4353.9), serum levels of IL-31 were 150.7 pg/ml (SD ± 178.2) and for IL-33 it was 42850.5 pg/ml (SD ± 11370.7) in hemodialysis patients; in comparison to serum levels of 7913.4 pg/ml (SD ± 3454.1), 67.1 pg/ml (SD ± 71.9) and 44875.9 pg/ml (SD ± 12114.6), respectively in the control group. IL-31 level was significantly higher in HD patients than in the control group (P = 0.0001), while the difference in the levels of IL-13 and IL-33 between the two groups were not statistically significant (P = 0.41 and 0.18, respectively). IL-13 had a statistically significant relationship with the itch score (P = 0.014) and the severity of itch (P = 0.03), while IL-31 and IL-33 were not statistically significant. CONCLUSION: UP is a complex and multifactorial problem. In patients with UP the high levels of IL-31 indicates a possible role in pathogenesis. IL-13 serum level on the other hand may be related to the severity of itch in these patients. Optimizing dialysis and targeting these cytokines may provide a potential therapeutic option especially in refractory UP. Further studies addressing these cytokines and their levels in response to various treatments may provide additional information on UP.

Interleukin-31: The "itchy" cytokine in inflammation and therapy.

The cytokine interleukin-31 has been implicated in the pathophysiology of multiple atopic disorders such as atopic dermatitis (AD), allergic rhinitis, and airway hyper-reactivity. In AD, IL-31 has been identified as one of the main "drivers" of its cardinal symptom, pruritus. Here, we summarize the mechanisms by which IL-31 modulates inflammatory and allergic diseases. TH 2 cells play a central role in AD and release high levels of TH 2-associated cytokines including IL-31, thereby mediating inflammatory responses, initiating immunoregulatory circuits, stimulating itch, and neuronal outgrowth through activation of the heterodimeric receptor IL-31 receptor A (IL31RA)/Oncostatin M receptor (OSMRß). IL31RA expression is found on human and murine dorsal root ganglia neurons, epithelial cells including keratinocytes and various innate immune cells. IL-31 is a critical cytokine involved in neuroimmune communication, which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti-IL-31 antibody. Accordingly, inhibition of IL-31-downstream signaling may be a beneficial approach for various inflammatory diseases including prurigo. However, as to whether downstream JAK inhibitors directly block IL-31-mediated-signaling needs to be clarified. Targeting the IL-31/IL31RA/OSMRß axis appears to be a promising approach for inflammatory, neuroinflammatory, and pruritic disorders in the future.

Implication of Increased Serum IL-31 for Primary Biliary Cholangitis.

Interleukin-31 (IL-31) has diverse biological functions. Increased IL-31 has been found in some skin and autoimmune diseases. There has been no study reporting the association between IL-31 and primary biliary cholangitis (PBC). This study was designed to determine serum IL-31 level and to explore its diagnostic value for PBC as well as the association of IL-31 with inflammatory and fibrotic progression. 60 PBC patients, 32 age- and sex-matched patients with chronic hepatitis B (CHB) and 30 age- and sex-matched healthy controls (HC) were recruited. The sera were detected for IL-31, IL-4, interferon gamma (IFN-γ), IL-17 and other laboratory indicators. Serum IL-31 levels were significantly higher in PBC patients (median, IQR, 20.6, 16.7-26.2, pg/ml) than CHB patients (median, IQR, 11.3, 8.0-13.0, pg/ml) and HC (median, IQR, 11.0, 10.0-12.2 pg/ml) (P < .001). Serum IL-31 performed well for identifying PBC, especially for antimitochondrial antibodies (AMA)-negative PBC with AUC of 0.900, optimal cutoff value of 13.6 pg/ml, sensitivity of 87.5% and specificity of 83.9%. Serum IL-31 was positively correlated with platelet count (r = 0.368, P = .004), but negatively with FIB4 (r = -0.307, P = .017) and histological stages (r = -0.364, P = .004) in PBC patients. It was also significantly correlated with IFN-γ (r = 0.404, P = .001) and IL-4 (r = 0.291, P = .026), but not with IL-17 (r = 0.151, P = .259) in PBC patients. Serum IL-31 is increased in and may be a useful marker for PBC, in particular, for AMA-negative PBC. Furthermore, it is inversely associated with fibrotic progression of PBC.

Fractional Carbon Dioxide Laser is Effective in Amelioration of Pruritus in Primary Cutaneous Amyloidosis: A Clinical and Biochemical Study.

BACKGROUND AND OBJECTIVES: Primary cutaneous amyloidosis (PCA) is a pruritic disease characterized by amyloid deposition in the skin. Interleukin-31 (IL-31) is a pruritus-mediating cytokine. Fractional carbon dioxide (CO2 ) laser has shown efficacy in the treatment of PCA regarding the clinical appearance, histological pattern, and pruritus. The aim of this study is to assess the effect of fractional CO2 laser on pruritus associated with PCA, and analyze whether this effect is related to IL-31 and IL-31 receptor (R) expression. STUDY DESIGN/MATERIALS AND METHODS: The study included 24 patients with PCA and 24 healthy controls. Each patient received four fractional CO2 laser sessions, 4 weeks apart, using the superficial ablative mode. Skin biopsies were taken from patients before and after treatment, as well as controls, for assessment of IL-31 and IL-31R by real-time polymerase chain reaction. RESULTS: Treatment resulted in significant improvement of all clinical parameters, including pruritus (P < 0.001). Patients before treatment had significantly higher IL-31 and IL-31R than controls (P = 0.000 for both). In addition, there was a statistically significant decrease in IL-31 and IL-31R after treatment than their values before treatment (P = 0.000 for both). CONCLUSION: This study confirms the therapeutic efficacy of fractional CO2 laser in treatment of PCA. Reduction of IL-31 and its receptor seems to be one of the involved mechanisms; however, its relation to improvement of pruritus is still not clear. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Interleukin-31, a Potent Pruritus-Inducing Cytokine and Its Role in Inflammatory Disease and in the Tumor Microenvironment.

Substantial new information has emerged supporting the fundamental role of the cytokine interleukin-31 (IL-31) in the genesis of chronic pruritus in a broad array of clinical conditions. These include inflammatory conditions, such as atopic dermatitis and chronic urticaria, to autoimmune conditions such as dermatomyositis and bullous pemphigoid, to the lymphoproliferative disorders of Hodgkin's disease and cutaneous T-cell lymphoma. IL-31 is produced in greatest quantity by T-helper type 2 (Th2) cells and upon release, interacts with a cascade of other cytokines and chemokines to lead to pruritus and to a proinflammatory environment, particularly within the skin. Antibodies which neutralize IL-31 or which block the IL-31 receptor may reduce or eliminate pruritus and may diminish the manifestations of chronic cutaneous conditions associated with elevated IL-31. The role of IL-31 in these various conditions will be reviewed.

Significance of interleukin-31 (IL-31) gene polymorphisms and IL-31 serum level in psoriasis in correlation with pruritus.

INTRODUCTION: Interleukin-31 (IL-31) impact on the development and clinical presentation of psoriasis as well as pruritus has not been widely investigated so far. AIM: To analyse IL-31 -1066G/A and -2057G/A promoter gene polymorphisms as well as serum IL-31 level and their correlation with severity of psoriasis and pruritus in the population of northern Poland. MATERIAL AND METHODS: The study included 300 psoriasis patients and 186 healthy volunteers. The polymorphisms were analysed using amplified refractory mutation system - polymerase chain reaction (ARMS-PCR) method. Serum levels of IL-31 were measured using the enzyme-linked immunosorbent assay (ELISA) test. RESULTS: The -1066 AA genotype of the IL-31 gene was statistically more frequent in patients and it increased the risk of psoriasis (OR = 1.80; p = 0.04). The GG genotype as well as G allele of the IL-31 -2057 gene polymorphism were rarely observed in psoriasis and were associated with a decreased risk of the disease (OR = 0.6, p = 0.007 and OR = 0.7, p = 0.01, respectively). Serum levels of IL-31 were significantly elevated in psoriasis patients (p < 0.000001), however, they did not correlate with the studied polymorphic variants of the IL-31 gene, severity of psoriasis, disease onset, presence of psoriatic arthritis and pruritus intensity. CONCLUSIONS: Distinct IL-31 promoter gene polymorphisms may be involved in psoriasis development. It seems that serum concentration of IL-31 may not be a reliable marker of psoriatic pruritus.