Skip to main content
Download PDF

Gamma-glutamyl transpeptidase and indirect bilirubin may participate in systemic inflammation of patients with psoriatic arthritis

Advances in Rheumatology volume 63, Article number: 53 (2023) Cite this article

Abstract

Background

Previous studies have suggested that systemic metabolic abnormalities are closely related to psoriatic arthritis (PsA). Gamma-glutamyl transpeptidase (GGT) and indirect bilirubin (IBIL), two essential active substances in hepatic metabolism that have been demonstrated as an oxidative and anti-oxidative factor respectively, have been proved to be involved in oxidative stress damage and inflammation in several human diseases. However, their role in PsA remains unclear.

Methods

In this retrospective comparative cohort study, a case group of 68 PsA patients and a control group of 73 healthy volunteers from the Third Hospital of Hebei Medical University were enrolled. Serum GGT, IBIL, GGT/IBIL ratio and C-reactive protein (CRP), a well applied bio-marker of systemic inflammatory in PsA, were compared between the two groups. Furthermore, the relationship of GGT, IBIL and GGT/IBIL with CRP were explored in PsA patients. Finally, the patients were divided into high inflammation group and low inflammation group according to the median value of CRP. Multivariate logistic regression analyses were used for the association of systemic inflammation level with GGT, IBIL and GGT/IBIL.

Results

Compared with healthy controls, PsA patients exhibited significantly higher serum GGT, GGT/IBIL, and CRP levels and lower IBIL levels. Serum GGT and GGT/IBIL were positively correlated with CRP, whereas IBIL were negatively correlated with CRP. Binary logistic regression analysis revealed that serum GGT was a risk factor for high CRP in PsA, whereas IBIL was a protective factor. Furthermore, GGT/IBIL was a better indicator of high CRP condition in PsA patients than either GGT or IBIL alone, as determined by the receiver operating characteristic curves.

Conclusion

GGT and IBIL may participate in the pathogenesis of PsA. Additionally, GGT, IBIL and the balance of the two may reflect systemic inflammation mediated by oxidative stress events related to metabolic abnormalities to a certain extent.

Introduction

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease that occurs in approximately 30% of patients with psoriasis [1, 2]. Currently, the pathogenesis of PsA is unclear. However, oxidative stress is considered an important factor associated with the pathogenesis of both psoriasis and PsA [3].

Gamma-glutamyl transpeptidase (GGT) is a crucial enzyme involved in the catabolism of glutathione (GSH), catalyzing the transfer of glutamyl to amino acids [4]. This process produces large amounts of reactive oxygen species (ROS), leading to the development of oxidative stress in the body [5]. The role of GGT in oxidative stress has received increasing attention in recent years, and previous studies have shown that serum GGT can predict the occurrence of metabolic syndrome, cardiovascular malfunctions and other diseases [6, 7]. However, only a few studies have analyzed the GGT expression in patients with PsA. Indirect bilirubin (IBIL) is the final product of heme catabolism. As early as 1987, Stocker et al. [8] suggested that bilirubin may be a natural antioxidant that can effectively eliminate free radicals and participate in the reduction of oxidative stress. It is known to have anti-inflammatory and immunosuppressive properties and plays a protective role in rheumatoid arthritis and polymyositis [9, 10]. Interestingly, previous reports have proposed contrasting roles for serum GGT and IBIL in metabolic syndrome and systemic lupus erythematosus [11, 12]. However, the roles of GGT and IBIL in PsA are currently unknown.

C-reactive protein (CRP) is a sensitive marker that reflects the inflammatory status of the body [13]. Previous studies have concluded that CRP is the best serum indicator of PsA activity [14]. Therefore, in this study, we used CRP as an indicator of the systemic inflammatory response to PsA and investigated the relationships between serum GGT, IBIL, and CRP levels in patients with PsA.

Materials and methods

Patients and healthy controls

We recruited patients with PsA who visited the Third Hospital of Hebei Medical University from January 2016 to December 2021. All patients met the 2006 Classification Criteria for Psoriatic Arthritis (CASPAR) [15]. Exclusion criteria included the following: pregnancy/breastfeeding, alcohol abuse, acute/chronic inflammatory disease, infection or trauma, hepatobiliary disease, renal insufficiency, coronary artery disease, cancer, hemolytic and autoimmune diseases, and treatment with antioxidants, non-steroidal anti-inflammatory drugs, steroidal drugs, immuno- suppressants, or biologics in the month prior to evaluation. Based on these criteria, 68 patients were enrolled in the study group. An additional 73 healthy volunteers were recruited from the physical examination center of our hospital as controls during the same period. Our trials were conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Third Hospital of Hebei Medical University (2022-023-1).

We retrospectively collected the personal and clinical data of all participants, including age, sex, and serum levels of GGT, IBIL, CRP, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Because GGT and IBIL are known to have oxidant and antioxidant properties, respectively, the GGT/IBIL ratio was included as an additional variable in the analysis.

Statistical analysis

All data were analyzed using SPSS 25.0 (SPSS Inc., Chicago, IL, USA). Normally distributed data were presented as mean ± standard deviation, and differences between groups were assessed using Student's t-tests. Nonparametric data were described by median values (interquartile range) and subjected to the Mann–Whitney U test. The chi-square test was used to compare the distribution of categorical variables between groups. Relationships between GGT, IBIL, GGT/IBIL, and CRP were analyzed by Spearman’s correlation analysis. The effect of GGT and IBIL on the severity of inflammation was evaluated through binary logistic regression. Finally, the receiver operating characteristic (ROC) curves were constructed based on the results of the logistic regression analysis to evaluate the predictive value of GGT, IBIL, and GGT/IBIL for the degree of inflammation in patients with PsA. All tests were two-tailed with a statistical significance threshold of P < 0.05.

Results

Baseline characteristics

The characteristics of 68 patients with PsA and 73 healthy controls are presented in Table 1. No significant differences were observed in the age and sex distributions between patients and controls (all P＞0.05). The levels of serum GGT, GGT/IBIL, and CRP were significantly higher (P = 0.036; P < 0.001; P < 0.001) in the patient group than in the control group, whereas IBIL concentrations were significantly lower (P < 0.001). ALT and AST levels showed no significant differences between the two groups (P = 0.068; P = 0.111).

Table 1 Clinical and laboratory data of PsA patients and controls
Full size table

Correlations of serum GGT, IBIL, and GGT/IBIL with CRP

Spearman correlation analysis was used to evaluate the associations of serum GGT, IBIL, and GGT/IBIL with CRP. We found that serum GGT levels were positively correlated with serum CRP levels (r = 0.4427, P < 0.001), while serum IBIL levels were negatively correlated with serum CRP levels (r = − 0.4187, P < 0.001). Furthermore, the ratio of GGT/IBIL was positively correlated with CRP levels (r = 0.6292, P < 0.001) (Fig. 1a–c).

Fig. 1
figure 1

Correlation between serum GGT, IBIL, and GGT/IBIL with CRP. a: Correlation analysis between GGT and CRP; b: correlation analysis between IBIL and CRP; c: correlation analysis between GGT/IBIL and CRP

Full size image

Relationship between GGT, IBIL, and the degree of inflammatory response in patients with PsA

To assess the relationship between GGT, IBIL levels and inflammation in patients with PsA, we used CRP levels as a measure of the inflammatory response and divided patients into two groups based on their median serum CRP concentration. No significant differences in age, gender, ALT level, or AST level between the CRP-low (PsA1) and CRP-high (PsA2) groups were detected (all P＞0.05). Serum GGT levels and GGT/IBIL were significantly higher in the PsA2 group than in the PsA1 group (P = 0.002; P < 0.001). Conversely, IBIL levels were significantly lower in the PsA2 group than in the PsA1 group (P = 0.003; Table 2). Multivariate logistic regression analysis adjusted for age, sex, and ALT, AST, GGT, and IBIL levels revealed that a high GGT level was a risk factor for high systemic inflammation in patients with PsA (OR = 1.073, 95% confidence interval [CI] 1.006–1.145, P = 0.032), whereas a high IBIL level was a protective factor (OR = 0.766, 95% CI 0.633–0.928, P = 0.006; Table 3). ROC curves showed that the area under the curve (AUC) value for GGT/IBIL (AUCGGT/IBIL = 0.814) was higher than that for GGT and IBIL (AUCGGT = 0.718; AUCIBIL = 0.707) (Fig. 2).

Table 2 Clinical and laboratory data of PsA1 and PsA2 patients
Full size table
Table 3 Logistic regression analysis of the PsA1 and PsA2 patient groups
Full size table
Fig. 2
figure 2

ROC curve representing effect of GGT, IBIL and GGT/IBIL on inflammatory response in PsA patients

Full size image

Discussion

PsA is a chronic inflammatory joint disease with complex pathogenesis. An increasing number of studies have recently proved that oxidative stress is associated with the pathogenesis of PsA. Firuzi et al. [16] found that plasma peroxide levels were significantly elevated and sulfhydryl levels were decreased in patients with PsA, suggesting that an imbalance of oxidative and antioxidative processes may contribute to PsA pathogenesis. Oxidative stress-associated ROS production triggers the activation of the nuclear factor-kappaB (NF-κB) signaling pathway in dendritic cells, macrophages, and other immune cells, which results in a release of inflammatory cytokines, such as interleukin 1 (IL-1) and tumor necrosis factor-α (TNF-α). These cytokines stimulate osteoclasts to invade adjacent cartilage and mediate bone resorption, leading to joint deformity and loss of function [17,18,19].

GGT transports glutamyl residues on cell membranes and is responsible for the catabolism of the antioxidant GSH in vivo. Studies have shown that GGT undergoes redox reactions when it hydrolyzes GSH and reduces Fe3+, which can produce large amounts of superoxide anions [4], leading to many events related to oxidative stress in the body. A previous study on coronary artery risk development in young adults suggested that increased serum GGT levels may serve as an early marker of oxidative stress and predict the serum levels of inflammatory factors, such as CRP [20]. Recent studies have demonstrated the involvement of GGT in the pathogenesis of cardiovascular and metabolic syndrome diseases through the oxidative stress reaction, concluding that GGT plays a pro-inflammatory role in these diseases [6, 7]. Furthermore, GGT levels were significantly increased in the inflamed synovial membranes of patients with rheumatoid arthritis. Moreover, injecting anti-GGT monoclonal antibodies into the intraperitoneal cavity of arthritic mice significantly reduced the number of osteoclasts and attenuated bone erosion [21]. Interestingly, GGT is an endogenous activator of Toll-like receptor 4-mediated osteoclastogenesis [22]. Our study builds upon these previous works, as we discovered a positive correlation between the levels of GGT and CRP in patients with PsA, indicating the GGT may serve as a risk factor for PsA-related inflammation.

IBIL is a powerful antioxidant, and the work by Zhao et al. [23] demonstrated that IBIL can directly scavenge superoxide anion radicals at the sites of inflammation. Furthermore, in a mouse model of autoimmune arthritis, exogenous IBIL injections significantly reduced oxidative DNA damage, neutrophil infiltration, and fibrin deposition in the joint cavity, leading to a decrease in inflammation and alleviating the symptoms of joint damage [24]. Additionally, IBIL has been shown to promote the expansion of regulatory T cells [25], which may disrupt the activation and proliferation of autoreactive T cells in PsA, thereby inhibiting the immune response. Moreover, in a study by Balta et al. [26], patients with psoriasis vulgaris exhibited decreased serum IBIL levels and elevated CRP levels, which is consistent with our findings. Thus, we conclude that IBIL plays a protective role in inflammatory and autoimmune diseases, including PsA.

At present, the specific mechanisms underlying the roles of GGT and IBIL in the inflammatory response of patients with PsA are unclear. However, we can glean some insights by connecting the findings of previous reports. The stimulation of bone marrow-derived macrophages with recombinant human GGT1 protein was shown to increase the expression of TNF-α, IL-1β, IL-6, and MIP-1α [22]. Both IL-1β and IL-6 trigger the differentiation of naïve T cells into Th17 cells. These cells secrete IL-17, as a key cytokine driving inflammation in PsA that functions in concert with other cytokines to increase synovial inflammation [27]. Furthermore, TNF-α and IL-6 activate Th22 cells, which release IL-22. This cytokine activates fibroblast-like synoviocytes through the PI3K-mTOR pathway, thereby inducing osteoclastogenesis [28, 29]. On a related note, Taniguchi et al. [30] demonstrated that in bone marrow stromal cells, GGT stimulates the expression of receptor activator of NF-κB ligand (RANKL), which is a major player in the differentiation of osteoblasts into osteoclasts [31]. In fact, RANKL expression in the synovial membrane was significantly increased in patients with PsA [32]. As an inhibitor of cytoplasmic protein kinase, IBIL could prevent the translocation of NF-κB to the nucleus by blocking the phosphorylation of IκB kinase, which is a master regulator of NF-κB signaling [33, 34]. Besides, NF-κB is also considered to be an important mediator of the pathogenesis of psoriasis [35]. When pro-inflammatory signals downstream of NF-κB are intercepted, the production of inflammatory cytokines such as TNF-α and IL-6 are impaired [36], while IL-6 in turn is the strongest stimulator of CRP formation [37]. The above findings may explain the negative correlation between IBIL and CRP levels identified in our study. Furthermore, our finding that GGT/IBIL was significantly positively correlated with CRP levels suggests that the ratio of GGT to IBIL better reflects the overall inflammatory status of PsA and indicates that the imbalance in oxidation/antioxidation ultimately leads to inflammatory reactions in vivo.

It is important to note that our study is not without limitations. As this was a retrospective study, the prognostic effect of serum GGT and IBIL on PsA could not be evaluated due to the lack of follow-up. In addition, relatively few patients were included in this study, and additional larger-scale studies are required to confirm these findings.

Conclusions

In conclusion, GGT and IBIL may participate in the pathogenesis of PsA. Additionally, GGT, IBIL and the balance of the two may reflect systemic inflammation mediated by oxidative stress events related to metabolic abnormalities to a certain extent.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. van der Heijde D, Gladman DD, Kavanaugh A, Mease PJ. Assessing structural damage progression in psoriatic arthritis and its role as an outcome in research. Arthritis Res Ther. 2020;22:18. https://doi.org/10.1186/s13075-020-2103-8.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Chimenti MS, Caso F, Alivernini S, De Martino E, Costa L, Tolusso B, et al. Amplifying the concept of psoriatic arthritis: the role of autoimmunity in systemic psoriatic disease. Autoimmun Rev. 2019;18:565–75. https://doi.org/10.1016/j.autrev.2018.11.007.

    Article  CAS  PubMed  Google Scholar 

  3. Lin X, Huang T. Oxidative stress in psoriasis and potential therapeutic use of antioxidants. Free Radic Res. 2016;50:585–95. https://doi.org/10.3109/10715762.2016.1162301.

    Article  CAS  PubMed  Google Scholar 

  4. Bulusu S, Sharma M. What does serum gamma-glutamyltransferase tell us as a cardiometabolic risk marker? Ann Clin Biochem. 2016;53:312–32. https://doi.org/10.1177/0004563215597010.

    Article  CAS  PubMed  Google Scholar 

  5. Drozdz R, Parmentier C, Hachad H, Leroy P, Siest G, Wellman M. γ-glutamyltransferase dependent generation of reactive oxygen species from a glutathione/transferrin system. Free Radic Biol Med. 1998;25:786–92. https://doi.org/10.1016/s0891-5849(98)00127-0.

    Article  CAS  PubMed  Google Scholar 

  6. Emdin M, Pompella A, Paolicchi A. Gamma-glutamyltransferase, atherosclerosis, and cardiovascular disease: triggering oxidative stress within the plaque. Circulation. 2005;112:2078–80. https://doi.org/10.1161/CIRCULATIONAHA.105.571919.

    Article  PubMed  Google Scholar 

  7. Kunutsor SK, Apekey TA, Seddoh D. Gamma glutamyltransferase and metabolic syndrome risk: a systematic review and dose-response meta-analysis. Int J Clin Pract. 2015;69:136–44. https://doi.org/10.1111/ijcp.12507.

    Article  CAS  PubMed  Google Scholar 

  8. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science. 1987;235:1043–6. https://doi.org/10.1126/science.3029864.

    Article  CAS  PubMed  Google Scholar 

  9. Juping D, Yuan Y, Shiyong C, Jun L, Xiuxiu Z, Haijian Y, et al. Serum bilirubin and the risk of rheumatoid arthritis. J Clin Lab Anal. 2017;31:8. https://doi.org/10.1002/jcla.22118.

    Article  CAS  Google Scholar 

  10. Peng Y-F, Zhang L, Pan G-G, Wei Y-S. A potential clinical usefulness of measuring serum bilirubin levels in patients with polymyositis. Eur Rev Med Pharmacol Sci. 2016;20:631–5.

    PubMed  Google Scholar 

  11. Giral P, Ratziu V, Couvert P, Carrie A, Kontush A, Girerd X, et al. Plasma bilirubin and gamma-glutamyltransferase activity are inversely related in dyslipidemic patients with metabolic syndrome: relevance to oxidative stress. Atherosclerosis. 2010;210:607–13. https://doi.org/10.1016/j.atherosclerosis.2009.12.026.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang W, Tang Z, Shi Y, Ji L, Chen X, Chen Y, et al. Association between gamma-glutamyl transferase, total bilirubin and systemic lupus erythematosus in Chinese women. Front Immunol. 2021;12:682400. https://doi.org/10.3389/fimmu.2021.682400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Anderson JL, Carlquist JF, Muhlestein JB, Horne BD, Elmer SP. Evaluation of C-reactive protein, an inflammatory marker, and infectious serology as risk factors for coronary artery disease and myocardial infarction. J Am Coll Cardiol. 1998;32:35–41. https://doi.org/10.1016/s0735-1097(98)00203-4.

    Article  CAS  PubMed  Google Scholar 

  14. Nell-Duxneuner VP, Stamm TA, Machold KP, Pflugbeil S, Aletaha D, Smolen JS. Evaluation of the appropriateness of composite disease activity measures for assessment of psoriatic arthritis. Ann Rheum Dis. 2010;69:546–9. https://doi.org/10.1136/ard.2009.117945.

    Article  PubMed  Google Scholar 

  15. Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H, et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 2006;54:2665–73. https://doi.org/10.1002/art.21972.

    Article  PubMed  Google Scholar 

  16. Firuzi O, Fuksa L, Spadaro C, Bousova I, Riccieri V, Spadaro A, et al. Oxidative stress parameters in different systemic rheumatic diseases. J Pharm Pharmacol. 2006;58:951–7. https://doi.org/10.1211/jpp.58.7.0010.

    Article  CAS  PubMed  Google Scholar 

  17. Yang Z, Min Z, Yu B. Reactive oxygen species and immune regulation. Int Rev Immunol. 2020;39:292–8. https://doi.org/10.1080/08830185.2020.1768251.

    Article  CAS  PubMed  Google Scholar 

  18. Zhou Q, Mrowietz U, Rostami-Yazdi M. Oxidative stress in the pathogenesis of psoriasis. Free Radic Biol Med. 2009;47:891–905. https://doi.org/10.1016/j.freeradbiomed.2009.06.033.

    Article  CAS  PubMed  Google Scholar 

  19. Sucur A, Jajic Z, Artukovic M, Matijasevic MI, Anic B, Flegar D, et al. Chemokine signals are crucial for enhanced homing and differentiation of circulating osteoclast progenitor cells. Arthritis Res Ther. 2017;19:142. https://doi.org/10.1186/s13075-017-1337-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lee DH, Jacobs DR Jr, Gross M, Kiefe CI, Roseman J, Lewis CE, et al. Gamma-glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Clin Chem. 2003;49:1358–66. https://doi.org/10.1373/49.8.1358.

    Article  CAS  PubMed  Google Scholar 

  21. Ishizuka Y, Moriwaki S, Kawahara-Hanaoka M, Uemura Y, Serizawa I, Miyauchi M, et al. Treatment with anti-gamma-glutamyl transpeptidase antibody attenuates osteolysis in collagen-induced arthritis mice. J Bone Miner Res. 2007;22:1933–42. https://doi.org/10.1359/jbmr.070726.

    Article  CAS  PubMed  Google Scholar 

  22. Moriwaki S, Into T, Suzuki K, Miyauchi M, Takata T, Shibayama K, et al. gamma-Glutamyltranspeptidase is an endogenous activator of Toll-like receptor 4-mediated osteoclastogenesis. Sci Rep. 2016;6:35930. https://doi.org/10.1038/srep35930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhao C, Huang H, Pan Q, Huang W, Peng W, Xu H, et al. Unconjugated bilirubin attenuates DSS-induced colitis potentially via enhancement of bilirubin reabsorption. Front Pharmacol. 2021;12:654808. https://doi.org/10.3389/fphar.2021.654808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sykora T, Babal P, Mikus-Kuracinova K, Drafi F, Ponist S, Dvorakova M, et al. Hyperbilirubinemia maintained by chronic supplementation of unconjugated bilirubin improves the clinical course of experimental autoimmune arthritis. Int J Mol Sci. 2021. https://doi.org/10.3390/ijms22168662.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Rocuts F, Zhang X, Yan J, Yue Y, Thomas M, Bach FH, et al. Bilirubin promotes de novo generation of T regulatory cells. Cell Transplant. 2010;19:443–51. https://doi.org/10.3727/096368909X484680.

    Article  PubMed  Google Scholar 

  26. Balta S, Balta I, Mikhailidis DP, Ozturk C, Demirkol S, Celik T, et al. Bilirubin levels and their association with carotid intima media thickness and high-sensitivity C-reactive protein in patients with psoriasis vulgaris. Am J Clin Dermatol. 2014;15:137–42. https://doi.org/10.1007/s40257-014-0069-5.

    Article  PubMed  Google Scholar 

  27. Benham H, Norris P, Goodall J, Wechalekar MD, FitzGerald O, Szentpetery A, et al. Th17 and Th22 cells in psoriatic arthritis and psoriasis. Arthritis Res Ther. 2013;15:R136. https://doi.org/10.1186/ar4317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Veale DJ, Fearon U. The pathogenesis of psoriatic arthritis. The Lancet. 2018;391:2273–84. https://doi.org/10.1016/s0140-6736(18)30830-4.

    Article  CAS  Google Scholar 

  29. Mitra A, Raychaudhuri SK, Raychaudhuri SP. IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR signaling cascade. Cytokine. 2012;60:38–42. https://doi.org/10.1016/j.cyto.2012.06.316.

    Article  CAS  PubMed  Google Scholar 

  30. Niida S, Kawahara M, Ishizuka Y, Ikeda Y, Kondo T, Hibi T, et al. Gamma-glutamyltranspeptidase stimulates receptor activator of nuclear factor-kappaB ligand expression independent of its enzymatic activity and serves as a pathological bone-resorbing factor. J Biol Chem. 2004;279:5752–6. https://doi.org/10.1074/jbc.M311905200.

    Article  CAS  PubMed  Google Scholar 

  31. Ash P, Loutit JF, Townsend KM. Osteoclasts derived from haematopoietic stem cells. Nature. 1980;283:669–70. https://doi.org/10.1038/283669a0.

    Article  CAS  PubMed  Google Scholar 

  32. Ritchlin CT, Haas-Smith SA, Li P, Hicks DG, Schwarz EM. Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Investig. 2003;111:821–31. https://doi.org/10.1172/JCI16069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jangi S, Otterbein L, Robson S. The molecular basis for the immunomodulatory activities of unconjugated bilirubin. Int J Biochem Cell Biol. 2013;45:2843–51. https://doi.org/10.1016/j.biocel.2013.09.014.

    Article  CAS  PubMed  Google Scholar 

  34. Hansen TW, Mathiesen SB, Walaas SI. Bilirubin has widespread inhibitory effects on protein phosphorylation. Pediatr Res. 1996;39:1072–7. https://doi.org/10.1203/00006450-199606000-00023.

    Article  CAS  PubMed  Google Scholar 

  35. Goldminz AM, Au SC, Kim N, Gottlieb AB, Lizzul PF. NF-kappaB: an essential transcription factor in psoriasis. J Dermatol Sci. 2013;69:89–94. https://doi.org/10.1016/j.jdermsci.2012.11.002.

    Article  CAS  PubMed  Google Scholar 

  36. Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol. 2009;1:a000034. https://doi.org/10.1101/cshperspect.a000034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Holzinger D, Foll D. Biomarkers for chronic inflammatory diseases. Z Rheumatol. 2015;74:887–96. https://doi.org/10.1007/s00393-015-0009-7. (quiz 97).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This research did not receive any specific grants from funding agencies representing the public, commercial, or not-for-profit sectors.

Author information

Author notes

  1. Xu Wang and Yan Mao have contributed equally to this study.

Authors and Affiliations

  1. Department of Dermatology, Third Hospital of Hebei Medical University, Shijiazhuang, China

    Xu Wang, Yan Mao, Shang Ji, Huanrong Hu, Qian Li, Lichao Liu, Shaomin Shi & Yaling Liu

Authors
  1. Xu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shang Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huanrong Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lichao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shaomin Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yaling Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XW and YM: writing the original manuscript. SS: conception and design. SJ: data collection. HH: performing statistical analysis. QL and LL: revising manuscript content. YL: approving the final version of manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Shaomin Shi or Yaling Liu.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Third Hospital of Hebei Medical University (Ethics number: 2022-023-1) and conducted in accordance to the Declaration of Helsinki principles.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, X., Mao, Y., Ji, S. et al. Gamma-glutamyl transpeptidase and indirect bilirubin may participate in systemic inflammation of patients with psoriatic arthritis. Adv Rheumatol 63, 53 (2023). https://doi.org/10.1186/s42358-023-00334-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s42358-023-00334-y

Keywords

Advances in Rheumatology

ISSN: 2523-3106