What’s Known

Opium consumption increases the risk of developing various cancers. Interleukin-33 and soluble ST2 play critical roles in cancer development.

What’s New

Serum levels of Interleukin-33 are significantly higher and soluble ST2 levels are significantly lower in opium users than non-opium users. Opium users diagnosed with cancer exhibited significantly higher levels of Interleukin-33 and lower levels of soluble ST2 than the opium users who were not diagnosed with cancer.

Introduction

Opium and opioid abuse are the major economic and health threats worldwide, especially in Asia and the Middle East. The highest rate of addiction to opium in the world has been reported to belong to Iran. Opioid addiction census has been reported to be 2.8% of the population over the age of 15, which accounts for 1.12 million adults, while the world consumption rate is about 0.5%. ¹ Among the health hazards of opium, the carcinogenic properties of this drug abuse have attracted a great deal of attention over the past decade. The association between opium use and several malignancies has been frequently reported. ^{2 - 4}

Opioids trigger numerous receptors in various organs. One of the systems that are affected by opioids is the immune system. There are three kinds of opioid receptors: μ, δ, and κ. The immune cells express many of these receptors. The immune function is regulated by the opioid peptides, which are secreted by the central nervous system. Furthermore, the opioid peptides produced by immunocytes may regulate the neuroendocrine system. ⁵ A previous study showed that subjects abusing opiates were more prone to various types of infection, since they confronted weak innate immunity. ⁶ Since many years ago, it has been believed that opioids suppress immune responses. However, many reports have supported the multi-effect of opioids on the immune system, such as modulatory, suppressive, and binary influences. As immune function is vital for the body on account of its effect on inflammation, tumor cells, and infectious diseases, the evaluation of opioids effects on the immune responses is of great importance. ⁵

Given the importance of inflammation in various cancers, numerous studies have been conducted on the role of different interleukins (ILs), especially IL-33 and ST2, in tumor genesis and metastasis. The family of IL-1 is a major part of the immune system. When inflammation occurs in the body, it is led by the family of IL-1 signaling pathway. ^{7 , 8} IL-33 is a novel member of the IL-1 family. ST2 is known as a receptor for IL-33. ⁹ Soluble IL-33 binds to soluble ST2 (sST2) in the blood. ¹⁰ IL-33 stimulates the cells of innate immunity to produce and release Th₂ cytokines, such as IL-4, IL-5, and IL-13. ⁹ Additionally, IL-33 stimulates Th₁ immune responses by inducing the release of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). ¹¹ Moreover, IL-33 is engaged in the maturation of dendritic and mast cells. ¹² It is also involved in controlling the accumulation of regulatory T cell, which is mediated by activation of the lymphoid cells. ^{13 , 14} Thus, IL-33 is crucial to both innate and adaptive immune responses. ¹⁵ It has the potential to activate the immune system under certain pathophysiological conditions, in addition to a dual role of both anti-inflammatory and pro-inflammatory in certain disorders. ¹⁶ The increased circulating IL-33 levels observed in gastric and lung cancer patients may be related to cancer progression through the ability of IL-33 to promote Th₂ immune responses, thereby creating the microenvironment for tumor growth and progression. ^{17 , 18} Elevated levels of IL-33 were observed in patients with gastric and lung cancer as well as hepatocellular carcinoma. ¹⁹

In this study, we assessed the effect of opium on serum levels of IL-33 and sST2 in order to speculate on the possible carcinogenic mechanism of opium.

Patients and Methods

The protocol of this study was reviewed and approved by the Ethics Committee of Shiraz University of Medical Sciences under the ethical code IR.SUMS.REC.1397.178. Each patient signed an informed consent form approved by the Local Institutional Review Board.

Collection of Human Blood Samples

Whole blood samples were obtained from the Fasa Cohort Study (FACS), which is a population-based cohort study enrolling 10157 participants within the age range of 35 to 70 in a region in southern Iran with high rates of opium use (24.1%). The details of the enrollment protocol and the cohort profile are described elsewhere. ^{20 - 22} In summary, a complete history of medical conditions and physical examination of the participants was registered, and a battery of laboratory tests at the enrollment time was obtained. The validated questionnaires, inquiring about physical activity, nutrition, social life, and other aspects of the participants’ daily activities, were filled by trained personnel at the time of enrollment. Biobanks consisting of whole blood and serum of all the participants were stored in cold rooms. The participants were being followed regularly for 10 years. ^{22 , 23} The daily use of different types of opium products was asked and registered per a validated questionnaire in FACS. ²¹ The samples were maintained at -70 ˚C in freezer. In a nested case-control design, 100 regular opium users were selected based on their opium use for over a year.

The subjects with over five years of history of opium abuse were enrolled in this study and followed up from 2014 to 2019. Opium users abused only opium and no other addictive substances. The individuals abusing opium with a history of any type of malignancy or those abusing substances besides opium were excluded from the study.

Herein, 100 controls were enrolled. The subjects’ characteristics were adjusted for their demographic data, such as sex, age, and place of residence, as well as their anthropometric properties. Moreover, history of illnesses (heart diseases, stroke, diabetes mellitus, different malignancies, and endocrine diseases) were adjusted between the groups and were extracted from the same cohort (FACS). Blood samples were extracted from the biobank and defrosted for biochemical analyses.

Serum Detection of IL-33 and sST2

IL-33 and sST2 were measured via commercial ELISA kit (IL-33 human ELISA kit, ab119547-IL-33, Abcam, USA, and human sST2 ELISA kit, Elabscience, USA) according to the manufacturer’s instructions, as described previously. ²⁴ Measurement of both sST2 and IL-33 was carried out based on the Sandwich-ELISA principle. For serum sST2 assessment, after adding the samples and standards to the micro ELISA plate wells, that were pre-coated with Human sST2 antibody and combined with the specific antibody, Avidin-Horseradish Peroxidase (HRP) was conjugated, and a biotinylated detection antibody were added successively and then were incubated. Afterward, the substrate solution was added to each well. The wells containing Human sST2, biotinylated detection antibody, and Avidin-HRP conjugate were blue in color. Stop solution was added to each well to terminate the enzyme-substrate reaction. The optical density (OD) of the produced yellow color was measured with a UV spectrophotometer at a wavelength of 450 nm.

For the IL-33 assay, after adding the samples and standards to each well pre-coated with IL-33 specific antibodies, the plates were incubated at the room temperature. A Biotin-conjugated anti-Human IL-33 detection antibody was added to each plate after washing them. Then, the plates were incubated once again at the room temperature. Subsequently, streptavidin-HRP conjugate was added to each well and incubated at the room temperature. Ultimately, TMB was added to each well in order to be catalyzed with HRP, so that we could obtain a product in blue color. The addition of the acidic stop solution changed its color into yellow, which was detected at a wavelength of 450 nm read with a UV-spectrophotometer.

Statistical Analysis

SPSS^® 21.0 for windows^® was utilized for data analysis (SPSS Inc., Chicago, Illinois). Continuous variables are presented as mean±SD. The normality of the data was analyzed using the Kolmogorov-Smirnov test. The IL-33 serum values passed Kolmogorov–Smirnov normality test, and a two-tailed Student’s t test was employed to compare this parameter between the groups. Since serum values of sST2 did not pass Kolmogorov–Smirnov normality test, Mann–Whitney U test was used to compare the level of sST2 between the groups. For the comparison of categorical parameters, Chi square test was used, with Yates or Fisher’s corrections applied when needed. Moreover, logistic regression analysis was performed to assess the influence of confounders on the incidence of cancer. P<0.05 were considered to be statistically significant.

Results

The demographic data of the enrolled subjects are demonstrated in table 1. No significant differences were observed between the two study groups regarding demographic and anthropometric or disease states.

The factors influencing serum concentrations of IL-33 and sST2, such as alcohol consumption, cigarette smoking, diabetes mellitus, endocrine and autoimmune diseases, inflammatory diseases, such as inflammatory bowel disease, and history of stroke did not vary significantly between the two study groups. Among the 200 studied individuals (100 non-opium users and 100 opium users), eight opium users were diagnosed with cancer through a five-year follow-up. Only one non-opium user got cancer during this period. Using logistic regression analysis, the incidence rate was 9.3 folds higher in opium users (P=0.040, RR=9.3; 95%CI=1.1-79.4). The malignancies diagnosed in the opium users were as follows: three individuals were diagnosed with bladder cancer, two developed laryngeal cancer, one developed esophageal cancer, one was diagnosed with gastric cancer, and one with lung cancer. Hodgkin’s lymphoma was diagnosed in one non-opium user. The demographic data of the subjects diagnosed with cancer were described previously. ²⁵

As shown in table 2, the serum level of IL-33 was significantly higher in the opium users than the healthy controls (P=0.001). Concerning the serum level of sST2, it was significantly lower in the subjects addicted to opium than that in the healthy volunteers (P=0.001). According to tables 2 and 3, the opium users diagnosed with cancer exhibited significantly higher serum concentrations of IL-33 and lower serum concentrations of sST2 than the cancer-free opium users (P=0.001).

Discussion

Our results revealed a significant increase in IL-33 serum concentration along with a remarkable decrease in sST2 serum concentration in the opium users than the control group. Additionally, higher levels of IL-33 and lower levels of sST2 were observed in the opium users diagnosed with cancer than those who were cancer-free.

Over the last decade, evidence has clearly indicated that inflammation plays a crucial role in tumor genesis, and that an inflammatory microenvironment is a vital element for the growth of all tumors. ²⁶ However, the exact causal molecular mechanisms still remain elusive. ²⁷

Among the health hazards of opium, the carcinogenic properties of this drug abuse have attracted a lot of attention over the past decade. Yet, the molecular mechanism of the relationship between opioids and cancer is obscure. Emphasizing the role of opioid receptors in cancer, the expression of μ-opioid receptor genes (MOR) has been observed in human lung, colon, and prostate cells leading to tumor growth and metastasis. ^{28 - 30} As questioned by Vallejo and colleagues, a clinically relevant dilemma is whether the immunosuppressive property of opioids, such as opium, is effective in the development of cancer. Opioids may modulate both cell-mediated and humoral immune responses. ³¹ There is a great body of evidence suggesting an increased expression of opioid receptors on lymphocytes and mononuclear phagocytes, which may modulate immune responses. ^{32 , 33} On the other hand, exogenous opioids affect receptor expression and secretion of inflammatory cytokines. ³¹

IL-33, a member of the IL-1 family, is an important mediator for the innate immune pathway, signaling Th₂ responses. IL-33 seems to have a double-action. Firstly, as a normal cytokine, it makes a complex by binding to its transmembrane receptor, ST2L; and secondly, as an intracellular nuclear factor, it can regulate gene transcription. ²⁶ Nonetheless, the soluble form of ST2 receptor, sST2, seems not to have a role in IL-33 signaling. It binds to IL-33 and inhibits its binding to ST2L. IL-33 is thought to function as an “alarmin” released after cell necrosis alerting the immune system of tissue damage or stress. It is clear that the strong stimulatory effects of IL-33 on some immune cell types are likely to influence inflammatory diseases. ³⁴ However, the precise role of IL-33 and IL-33/ST2 signaling pathways in cancer is still not well understood.

Elevated serum levels of IL-33 have been demonstrated in several types of cancer. Activation of ST2 receptor by IL-33 stimulates the growth and metastasis of various cancers ^{35 - 37} and inhibits the anti-tumor immunity. ³⁸ Therefore, it has been proposed as an important effector in tumor progression. By binding to the sST2 receptor, IL-33 activates the ST2–ERK1/2 pathway and consequently upregulates the production of two inflammatory mediators, namely MMP-3 and IL-6, which may contribute to the pathophysiologic effects of IL-33 in gastric cancer. ³⁹ Interestingly, in vitro data has demonstrated that knocking down IL-33 decreased the invasion and metastatic capacity in esophageal cancer cells, while overexpression of IL-33 showed a contradictory effect. ⁴⁰ Regarding the signaling of IL-33/sST2 in cancer, IL-33 recruits IL-1R-associated kinase 1 and 4 to the receptor complex in the cytoplasmic region of ST2 by binding to the IL-33 receptor, triggering several signaling downstream molecules, such as NF-κB. This process enhances the expression of different proteins, which could lead to inflammation and promote metastasis. ^{41 , 42}

Furthermore, the over-expression of IL-33 causes the production of the immature dendritic cell. These cells are responsible for the generation of T_reg and thus, tumor progression and metastasis. ³⁸

It has been stated that ST2 deficiency leads to an increase in pro-inflammatory cytokines, such as TNF-α and IL-17, ³⁸ which are believed to play a pivotal role in cancer promotion and progression. ^{43 , 44}

The ability of IL-33 to activate the cells of both the innate and adaptive immune system makes IL33 an important cytokine in the initiation and spread of inflammation. ⁴⁵ Given the significant role of IL-33 in tumor progression and metastasis, ^{17 , 46} this cytokine could be a good candidate as a prognostic biomarker. Since in the course of inflammation, sST2 binds to IL-33 in the blood, the harmful effects of IL-33 in the body are reduced. ^{47 , 48} Therefore, the obtained results herein, showing lower levels of sST2 and as a result, higher free serum levels of IL-33 in the opium users may propose a potential biomarker property for IL-33 and sST2 in the early detection of cancer in opium users. The major limitation of our study is the small sample size. It could be suggested to study the signaling of IL-33/sST2 in detail in opium users in future research.

Conclusion

Our findings suggested a predictive value of serum IL-33/sST2 levels in opium users for the development of cancer. It may be postulated that manipulating the IL-33/sST2 pathway has preventive and/or therapeutic implications in cancers, especially in opium users.

Acknowledgment

The authors would like to thank the Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, for their financial support. This study was a part of the Pharm D thesis of Kimia Javdani (Project no. 14814).

Authors’ Contribution

N.F: Conception and design of the work, acquisition, analysis and interpretation of data for the work, drafting and revising the manuscript critically for important intellectual content; K.J: Acquisition, analysis and interpretation of data for the work; drafting and revising the manuscript critically for important intellectual content; A.D: Interpretation of data for the work; revising the manuscript critically for important intellectual content. All authors have read and approved the final manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflict of Interest

None declared.

References

1. Amin-Esmaeili M, Rahimi-Movaghar A, Sharifi V, Hajebi A, Radgoodarzi R, Mojtabai R, et al. Epidemiology of illicit drug use disorders in Iran: prevalence, correlates, comorbidity and service utilization results from the Iranian Mental Health Survey. Addiction. 2016; 111:1836-47. DOI | PubMed
2. Moossavi S, Mohamadnejad M, Pourshams A, Poustchi H, Islami F, Sharafkhah M, et al. Opium Use and Risk of Pancreatic Cancer: A Prospective Cohort Study. Cancer Epidemiol Biomarkers Prev. 2018; 27:268-73. Publisher Full Text | DOI | PubMed
3. Kamangar F, Shakeri R, Malekzadeh R, Islami F. Opium use: an emerging risk factor for cancer?. Lancet Oncol. 2014; 15:e69-77. DOI | PubMed
4. Mahmoodpoor A, Golzari SE. Epigenetics, opium, and cancer. Lancet Oncol. 2014; 15:e153. DOI | PubMed
5. Liang X, Liu R, Chen C, Ji F, Li T. Opioid System Modulates the Immune Function: A Review. Transl Perioper Pain Med. 2016; 1:5-13. Publisher Full Text | PubMed
6. Wang J, Barke RA, Ma J, Charboneau R, Roy S. Opiate abuse, innate immunity, and bacterial infectious diseases. Arch Immunol Ther Exp (Warsz). 2008; 56:299-309. DOI | PubMed
7. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009; 27:519-50. DOI | PubMed
8. Dinarello CA. Overview of the interleukin-1 family of ligands and receptors. Semin Immunol. 2013; 25:389-93. DOI | PubMed
9. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005; 23:479-90. DOI | PubMed
10. Mueller T, Jaffe AS. Soluble ST2--analytical considerations. Am J Cardiol. 2015; 115:8B-21B. DOI | PubMed
11. Bourgeois E, Van LP, Samson M, Diem S, Barra A, Roga S, et al. The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-gamma production. Eur J Immunol. 2009; 39:1046-55. DOI | PubMed
12. Saluja R, Hawro T, Eberle J, Church MK, Maurer M. Interleukin-33 promotes the proliferation of mouse mast cells through ST2/MyD88 and p38 MAPK-dependent and Kit-independent pathways. J Biol Regul Homeost Agents. 2014; 28:575-85. PubMed
13. Cayrol C, Girard JP. Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family. Immunol Rev. 2018; 281:154-68. DOI | PubMed
14. Braun H, Afonina IS, Mueller C, Beyaert R. Dichotomous function of IL-33 in health and disease: From biology to clinical implications. Biochem Pharmacol. 2018; 148:238-52. DOI | PubMed
15. Pinto SM, Subbannayya Y, Rex DAB, Raju R, Chatterjee O, Advani J, et al. A network map of IL-33 signaling pathway. J Cell Commun Signal. 2018; 12:615-24. Publisher Full Text | DOI | PubMed
16. Miller AM, Asquith DL, Hueber AJ, Anderson LA, Holmes WM, McKenzie AN, et al. Interleukin-33 induces protective effects in adipose tissue inflammation during obesity in mice. Circ Res. 2010; 107:650-8. Publisher Full Text | DOI | PubMed
17. Liu J, Shen JX, Hu JL, Huang WH, Zhang GJ. Significance of interleukin-33 and its related cytokines in patients with breast cancers. Front Immunol. 2014; 5:141. Publisher Full Text | DOI | PubMed
18. Schwartz C, O’Grady K, Lavelle EC, Fallon PG. Interleukin 33: an innate alarm for adaptive responses beyond Th2 immunity-emerging roles in obesity, intestinal inflammation, and cancer. Eur J Immunol. 2016; 46:1091-100. DOI | PubMed
19. Chen XJ, Huang YD, Li N, Chen M, Liu F, Pu D, et al. Correlations between serum IL33 and tumor development: a meta-analysis. Asian Pac J Cancer Prev. 2014; 15:3503-5. DOI | PubMed
20. Farjam M, Bahrami H, Bahramali E, Jamshidi J, Askari A, Zakeri H, et al. A cohort study protocol to analyze the predisposing factors to common chronic non-communicable diseases in rural areas: Fasa Cohort Study. BMC Public Health. 2016; 16:1090. Publisher Full Text | DOI | PubMed
21. Kazemi M, Bazyar M, Naghizadeh MM, Dehghan A, Rahimabadi MS, Chijan MR, et al. Lipid profile dysregulation in opium users based on Fasa PERSIAN cohort study results. Sci Rep. 2021; 11:12058. Publisher Full Text | DOI | PubMed
22. Poustchi H, Eghtesad S, Kamangar F, Etemadi A, Keshtkar AA, Hekmatdoost A, et al. Prospective Epidemiological Research Studies in Iran (the PERSIAN Cohort Study): Rationale, Objectives, and Design. Am J Epidemiol. 2018; 187:647-55. Publisher Full Text | DOI | PubMed
23. Eghtesad S, Mohammadi Z, Shayanrad A, Faramarzi E, Joukar F, Hamzeh B, et al. The PERSIAN Cohort: Providing the Evidence Needed for Healthcare Reform. Arch Iran Med. 2017; 20:691-5. PubMed
24. Firouzabadi N, Dashti M, Dehshahri A, Bahramali E. Biomarkers of IL-33 and sST2 and Lack of Association with Carvedilol Therapy in Heart Failure. Clin Pharmacol. 2020; 12:53-8. Publisher Full Text | DOI | PubMed
25. Firouzabadi N, Haghnegahdar M, Khalvati B, Dehshahri A, Bahramali E. Overexpression of Adiponectin Receptors in Opium Users with and without Cancer. Clin Pharmacol. 2020; 12:59-65. Publisher Full Text | DOI | PubMed
26. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008; 454:436-44. DOI | PubMed
27. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010; 140:883-99. Publisher Full Text | DOI | PubMed
28. Ecimovic P, Murray D, Doran P, McDonald J, Lambert DG, Buggy DJ. Direct effect of morphine on breast cancer cell function in vitro: role of the NET1 gene. Br J Anaesth. 2011; 107:916-23. DOI | PubMed
29. Mathew B, Lennon FE, Siegler J, Mirzapoiazova T, Mambetsariev N, Sammani S, et al. The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation. Anesth Analg. 2011; 112:558-67. Publisher Full Text | DOI | PubMed
30. Nylund G, Pettersson A, Bengtsson C, Khorram-Manesh A, Nordgren S, Delbro DS. Functional expression of mu-opioid receptors in the human colon cancer cell line, HT-29, and their localization in human colon. Dig Dis Sci. 2008; 53:461-6. DOI | PubMed
31. Vallejo R, de Leon-Casasola O, Benyamin R. Opioid therapy and immunosuppression: a review. Am J Ther. 2004; 11:354-65. DOI | PubMed
32. Peterson PK, Molitor TW, Chao CC. The opioid-cytokine connection. J Neuroimmunol. 1998; 83:63-9. DOI | PubMed
33. Carr DJ, DeCosta BR, Kim CH, Jacobson AE, Guarcello V, Rice KC, et al. Opioid receptors on cells of the immune system: evidence for delta- and kappa-classes. J Endocrinol. 1989; 122:161-8. DOI | PubMed
34. Miller AM. Role of IL-33 in inflammation and disease. J Inflamm (Lond). 2011; 8:22. Publisher Full Text | DOI | PubMed
35. Bergis D, Kassis V, Ranglack A, Koeberle V, Piiper A, Kronenberger B, et al. High Serum Levels of the Interleukin-33 Receptor Soluble ST2 as a Negative Prognostic Factor in Hepatocellular Carcinoma. Transl Oncol. 2013; 6:311-8. Publisher Full Text | DOI | PubMed
36. Cui G, Ren J, Xu G, Li Z, Zheng W, Yuan A. Cellular and clinicopathological features of the IL-33/ST2 axis in human esophageal squamous cell carcinomas. Cancer Cell Int. 2018; 18:203. Publisher Full Text | DOI | PubMed
37. Sun P, Ben Q, Tu S, Dong W, Qi X, Wu Y. Serum interleukin-33 levels in patients with gastric cancer. Dig Dis Sci. 2011; 56:3596-601. DOI | PubMed
38. Jovanovic IP, Pejnovic NN, Radosavljevic GD, Arsenijevic NN, Lukic ML. IL-33/ST2 axis in innate and acquired immunity to tumors. Oncoimmunology. 2012; 1:229-31. Publisher Full Text | DOI | PubMed
39. Yu XX, Hu Z, Shen X, Dong LY, Zhou WZ, Hu WH. IL-33 Promotes Gastric Cancer Cell Invasion and Migration Via ST2-ERK1/2 Pathway. Dig Dis Sci. 2015; 60:1265-72. DOI | PubMed
40. Yue Y, Lian J, Wang T, Luo C, Yuan Y, Qin G, et al. Interleukin-33-nuclear factor-kappaB-CCL2 signaling pathway promotes progression of esophageal squamous cell carcinoma by directing regulatory T cells. Cancer Sci. 2020; 111:795-806. Publisher Full Text | DOI | PubMed
41. Zhang JF, Wang P, Yan YJ, Li Y, Guan MW, Yu JJ, et al. IL33 enhances glioma cell migration and invasion by upregulation of MMP2 and MMP9 via the ST2-NF-kappaB pathway. Oncol Rep. 2017; 38:2033-42. Publisher Full Text | DOI | PubMed
42. Gao X, Wang X, Yang Q, Zhao X, Wen W, Li G, et al. Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells. J Immunol. 2015; 194:438-45. Publisher Full Text | DOI | PubMed
43. Balkwill F. TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev. 2006; 25:409-16. DOI | PubMed
44. Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau CS, et al. IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature. 2015; 522:345-8. Publisher Full Text | DOI | PubMed
45. Liew FY, Pitman NI, McInnes IB. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol. 2010; 10:103-10. DOI | PubMed
46. Hu LA, Fu Y, Zhang DN, Zhang J. Serum IL-33 as a diagnostic and prognostic marker in non- small cell lung cancer. Asian Pac J Cancer Prev. 2013; 14:2563-6. DOI | PubMed
47. Hayakawa H, Hayakawa M, Kume A, Tominaga S. Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem. 2007; 282:26369-80. DOI | PubMed
48. Oshikawa K, Yanagisawa K, Tominaga S, Sugiyama Y. Expression and function of the ST2 gene in a murine model of allergic airway inflammation. Clin Exp Allergy. 2002; 32:1520-6. DOI | PubMed