Correlations Between Serum IL 33 and Tumor Development : a Meta-analysis

Interleukin-33 (IL-33). is a novel cytokine belonging to the IL-1 family which was found in 2005 (Schmitz et al., 2005). It is found in various cells included fibroblasts, bronchial and epithelial cells, endothelial cells, and some immune cells, including macrophages and dendritic cells (Kakkar and Lee 2008). IL-33 is a multifunctional cytokine in immune regulation that activates Th1 cells, Th2 cells, CD8+T cells and NK cells (Chackerian et al., 2007; Bourgeois et al., 2009; Liew, et al., 2010; Bonilla et al., 2012). Accumulated data also demonstrated that immune cells play important role in tumor progress and prognosis (Dobrzanski et al., 2006; Williams and Bevan 2007). Moreover, IL-33 participates in many diseases with dual, proinflammatory or protective roles depending on the cellular and cytokine context, including infectionrelated diseases (such as parasitic and viral infection). (Walzl et al., 2001; Humphreys et al., 2008; Liew et al., 2010). However, the role of IL-33 in tumor progress and prognosis is unclear. In this paper, we were attempt to reveal the role of IL-33 in tumor progress and prognosis by a meta analysis.


Introduction
. is a novel cytokine belonging to the IL-1 family which was found in 2005 (Schmitz et al., 2005).It is found in various cells included fibroblasts, bronchial and epithelial cells, endothelial cells, and some immune cells, including macrophages and dendritic cells (Kakkar and Lee 2008).IL-33 is a multifunctional cytokine in immune regulation that activates Th1 cells, Th2 cells, CD8+T cells and NK cells (Chackerian et al., 2007;Bourgeois et al., 2009;Liew, et al., 2010;Bonilla et al., 2012).Accumulated data also demonstrated that immune cells play important role in tumor progress and prognosis (Dobrzanski et al., 2006;Williams and Bevan 2007).Moreover, IL-33 participates in many diseases with dual, proinflammatory or protective roles depending on the cellular and cytokine context, including infectionrelated diseases (such as parasitic and viral infection).(Walzl et al., 2001;Humphreys et al., 2008;Liew et al., 2010).However, the role of IL-33 in tumor progress and prognosis is unclear.
In this paper, we were attempt to reveal the role of IL-33 in tumor progress and prognosis by a meta analysis.

Materials and Methods
A computerized literature search was conducted using Pubmed, MEDLINE, EMBASE and Chinese databases (including CNKI and WanFang database).from 1 January 2000 through 31 October 2013.The search strategy used

Data Extraction
Two investigators independently performed the data extraction.When discrepancies were found, a third investigator would make the definitive decision for data extraction.The extracted information included: the first author's last name, publication year, study location, participant characteristics (age and sex), sample size, follow-up (yes or no), variables adjusted in the analysis.

Statistical analysis
The main outcomes were analyzed by using RveMan 5. 1 software.Chi-square and I-square tests were used to assess heterogeneity amongst the RCTs, when the results were P>0.1 and I 2 <50%, it mains there were no heterogeneity, and then fixed-effect model was analyzed; when P<0.1 and I 2 >50%, there were significant heterogeneity exist, we used random-effects statistical model.

Methodological quality
The characteristics of the included studies and Jadad score are shown in Table 1.No studies described randomized methods and allocation concealment.Five studies adopted double-blind, and the baseline of all researches was similar.All articles used the intent-to-treat analysis.The outcomes included the correlation between IL33 level and tumor, survival time, the correlation between IL33 level and tumor stage, the correlation between IL33 level and tumor metastasis.

The meta-analysis results
The correlation between IL33 expression level and lots of tumor: All of the eight included papers (Sun et al., 2011;Naumnik et al., 2012;Zhang et al., 2012;Bergis et al., 2013;Chen et al., 2013;Gangemi et al., 2013;Hu et al., 2013;Santulli et al., 2013).reported the correlation between IL33 expression level and tumors, there were 656 patients with tumors and 625 healthy people.The metaanalysis results shown that IL33 level in tumors patients is higher than that in healthy people (P<0.00001,95%CI (96. 55,117. 78)) The survival time: In here, two papers (Sun et al., 2011;Hu et al., 2013).reported the correlation between IL33 expression level and survival time in tumors cases.The meta-analysis results shown there were not significantly differences between IL33 level and survival time (P=0.18,95%CI (-38.57, 7. 10)).

The correlation between IL-33 level and tumor stage:
There were three researches (Sun et al., 2011;Bergis et al., 2013;Hu et al., 2013).described the correlation between IL33 level and tumor stage.The meta-analysis results shown that the IL33 level in I-II stage is not higher than III-IV stage (P=0.29,95%CI (-35.47, 10.65)).
The correlation between IL33 expression level and tumor metastasis: There were two researches (Sun et al., 2011;Zhang et al., 2012).reported the correlation between IL33 level and tumor metastasis.The meta-analysis results shown that there were not significant differences between IL33 level and tumor metastasis (P=0.26,95%CI (-186.79,50.50)).

Discussion
In this meta-analysis paper, we reported the IL-33 expression level is higher in tumor patients than that in healthy people, however, there are not significant differences between IL-33 expression level and survival time, tumor stage and tumor metastasis.
Interleukin-33 (IL-33). is a recently finding cytokine with lots of functions.IL-33 has been reported as a potent inducer of Th2 immune responses as well as "alarmin" cytokine released from necrotic cells (Arshad et al., 2012;Lopetuso et al., 2012;Roy et al., 2014).Recently, some   .2014.15.8.3503 Correlations Between Serum IL33 and Tumor Development: a Meta-analysis researches reported that IL-33 is play important role in tumorigenesis and tumor progress (Chen et al., 2013;Jovanovic et al., 2014)Serum IL-33 may be a useful indicator for prognosis of tumor (Sun et al., 2011).In here, our meta-analysis included eight papers results shown that IL33 expression level is higher in tumor patients that in healthy people, so, there is a clinical value that IL-33 can be as a potential diagnostic for tumor patient.Therefore, cumulative meta-analysis showed an increased accuracy with larger samples aggregated for the correlation in the estimate of the effects in IL-33 cytokine.However, there were not significant difference between IL-33 expression level and survival time, tumor stage and tumor metastasis, perhaps because less papers were included into this paper.Therefore, more reporting correlation between two should be needed.
IL-33 signaling is mediated via its receptor ST2L.The role of IL-33/ST2 axis has recently been implicated in cancer, but with limited data.The Bergis et al., (Bergis et al., 2013).reported the ST2 level is higher in tumor patients than in healthy people (1079.6±310.1 vs 218.6±45.8, P<0.05).High ST2 levels have been found in malignant patients with lung cancer (Oshikawa et al., 2002).Moreover, it has been demonstrated that a lack of ST2 in ST-/-mice is associated with suppressed breast cancer proression and metastasis (Jovanovic et al., 2011).However, there were limited documents describing the relation between ST2 and tumor.So, the correlation between ST2 level and tumor was not included into this meta-analysis.
In conclusion, this meta-analysis suggest that the IL33 level is higher in tumor patients than health people.However, there were not correlation between IL33 level and survival time, metastasis and stage of tumor.Moreover, more related documents should be supplemented.

Figure 1 .Figure
Figure 1.The Meta-analysis Result of IL33 Level in Tumor