Interleukin-22 Is Frequently Expressed in Small- and Large-Cell Lung Cancer and Promotes Growth in Chemotherapy-Resistant Cancer Cells

Introduction: In lung cancer, interleukin-22 (IL-22) expression
within primary tissue has been demonstrated, but the frequency and
the functional consequence of IL-22 signaling have not been
addressed. This study aims at analyzing the cellular effects of
IL-22 on lung carcinoma cell lines and the prognostic impact of
IL-22 tissue expression in lung cancer patients. Methods:
Biological effects of IL-22 signaling were investigated in seven
lung cancer cell lines by Western blot, flow cytometry, real-time
polymerase chain reaction, and proliferation assays. Tumor tissue
specimens of two cohorts with a total of 2300 lung cancer patients
were tested for IL-22 expression by immunohistochemistry. IL-22
serum concentrations were analyzed in 103 additional patients by
enzyme-linked immunosorbent assay. Results: We found the IL-22
receptor 1 (IL-22-R1) to be expressed in six of seven lung cancer
cell lines. However IL-22 signaling was functional in only four
cell lines, where IL-22 induced signal transducer activator of
transcription 3 phosphorylation and increased cell proliferation.
Furthermore, IL-22 induced the expression of antiapoptotic B-cell
lymphoma 2, but did not rescue tumor cells from carboplatin-induced
apoptosis. Cisplatin-resistant cell lines showed a significant
up-regulation of IL-22-R1 along with a stronger proliferative
response to IL-22 stimulation. IL-22 was preferentially expressed
in small- and large-cell lung carcinoma (58% and 46% of cases,
respectively). However, no correlation between IL-22 expression by
immunohistochemistry and prognosis was observed. Conclusion: IL-22
is frequently expressed in lung cancer tissue. Enhanced IL-22-R1
expression and signaling in chemotherapy-refractory cell lines are
indicative of a protumorigenic function of IL-22 and may contribute
to a more aggressive phenotype.