A full understanding of the pathogenesis of CSU has yet to be achieved. In the present study, to gain better understanding of the role of cytokines in immunopathogenesis of CSU we aimed to determine whether CSU is associated with alterations in IL-17, IL-31, and IL-33. The results of our study showed that plasma levels of IL-17, IL-31, and IL-33 were significantly elevated in patients with CSU. Severe group of CSU patients had significantly higher IL-17 levels compared with the moderate and mild group, and significantly higher IL-33 concentration than the mild group of CSU patients.
The IL-17 levels were significantly higher in CSU patients compared with the control group, and severe group had significantly higher IL-17 levels compared with the other two groups of CSU patients. In agreement with our results, many studies showed that the IL-17 levels of CU patients was higher than that of control17,18,19, and there were significant positive correlation between serum IL-17, IL-23, TNF-α and disease activity18. In another report, IL-17 were significantly higher in autologous serum skin test (ASST) positivity than in ASST negative CSU patients20. Moreover, patients with CSU and ASST positivity, showed increased circulating levels of TNF-α, IL-1β and IL-6. These pro-inflammatory cytokines, in turn, are known to be induced by IL-17, which may contribute to the inflammatory profile founded in CSU17.
The important role of IL-31 in atopic dermatitis, in particular its impact on intensity of pruritus, is well known. An enhanced expression of the specific IL-31RA was discovered in cells of the human and murine dorsal root ganglia and in murine primary afferent fibers of the spinal cord and dermis that are proposed to be involved in the sensation of itch21,22. Furthermore, IL-31 antibodies have been shown to reduce itch significantly in a mouse model of AD23, confirming in patients with moderate-to-severe AD very recently24. Our results agreed with a previous study, in which the researchers demonstrated that IL-31 levels in CSU patients were significantly higher compared with those of controls25. However, there was no difference in IL-31 plasma levels in ASST positive or negative CU patients25. We could not find a correlation between IL-31 plasma levels and the urticaria activity, confirming a previous report26, but if regarding only pruritus, severe group of CSU patients had significantly higher IL-31 levels than the mild group. This may be attributed to the fact that IL-31 is contribute to itching.
IL-33 is being increasingly recognized as an important inflammatory cytokine. The plasma levels of IL-33 were significantly higher in patients with CSU, and severe group had significantly higher concentration compared to the mild group of CSU patients. In support of our finding, elevation of IL-33 was recently demonstrated in the lesional skin of CSU patients27. Besides, among the patients who had received desloratadine for two weeks, there was a significant reduction in IL33 levels of CSU patients28. IL-33 induces increased release of Th2 cytokines such as IL-5 and IL-13 from Th2 cells in vitro and elevated levels of plasma IgE and blood eosinophils in vivo29. IL-33 also causes activation, maturation, and Th2 cytokine production in mast cells30 and induces eosinophil-dependent cutaneous fibrosis27. Thus, IL-33 may play a pivotal role in the development of inflammatory reactions in CSU.
Inconsistent with our results, there were studies demonstrated the plasma IL-17 levels in CSU patients were not differ from the healthy control20,31 or even lower32. Besides, two reports showed that there was no significant difference in plasma IL-33 levels between patients with urticaria and control subjects33,34. The probable cause of the different result may be impact of genetic variation in the study population or the study was conducted on a small number of patients32.
Intriguingly, IL-33 levels were both correlated with IL-17 and IL-31 in CSU patients. Many studies provided indirect evidence for a functional link between these cytokines in many human diseases. Vocca et al. reported IL-33/ST2 axis was involved in Th2/IL-31 and Th17 immune response during the progression of allergic airway disease35. Nygaard et al. found a moderate, positive correlation between IL-33 and IL-31 in atopic dermatitis36. These authors speculate that the activation of the IL-33-ST2 axis, as a biomarker of Th2/IL-31 immune response, may be a critical crossroad between the immune system and epidermal homoeostasis36. On the other hand, Meephansan et al. found IL-17A induced IL-33 in epidermis through EGFR, EPK, p38 and JAK/STAT1 pathways, which were necessary for induction of IL-3337. There may be a functional link between these cytokines, but the exact mechanism is not yet clear and needs further study.
A correlation between IL-33 and IgE has been reported. A study demonstrated that mast cells produce IL-33 after IgE-mediated activation and that the IL-33/ST2 pathway was critical for the progression of IgE-dependent inflammation38. Futhermore, IL-33 enhances IgE-mediated degranulation and migration as well as IgE- and IL-3-mediated cytokine and chemokine production in human and mouse basophils39. On the other hand, long-term exposure of human and mouse muscle cell to IL-33 resulted in attenuation of IgE/Ag-FcεRI-mediated degranulation due to down-regulation of PLCγ1 and Hck expression, although short term exposure to IL-33 did not influence that degranulation directly40. In our study, we found the IL-33 levels in the total IgE positive group were significantly higher than that of negative group, providing evidence for this functional link between IL-33 and IgE in CSU.
Our study has two limitations. One is the relatively small number of study subjects. The other is the absence of a positive control group, such as atopic dermatitis or psoriasis as an inflammatory dermatosis. Therefore, further studies with a larger sample size and a positive control group are required to confirm our results.
In summary, our results showed high plasma levels of IL-17, IL-31, and IL-33 among CSU patients which may highlight a functional role of these cytokines in the pathogenesis of this common skin disease, and may provide the rationale for new treatment strategies in chronic urticaria. However, more studies are needed on more patients to study different Th1, Th2 and Th17 cytokines in plasma and skin of CSU patients.