Functional interleukin-4 receptor and interleukin-2 receptor common gamma chain in human gastric carcinoma: a possible mechanism for cytokine-based therapy

Interleukin (IL)-2 and IL-4 play a critical role in the regulation of the immune response. Yet both of the receptors for these cytokines have been found on nonhematopoietic cells, including human gastric carcinoma cell lines and tissue specimens. IL-4 causes Gl phase cell cycle arrest of gastric carcinoma; the effect directly correlates with the expression of IL-4 receptor (IL4R) and is seen within 48 hours after treatment. Cells lacking IL-4R are unaffected by IL-4. We examined signal transduction pathways employed by IL-4 that may account for cell cycle arrest of an established human gastric carcinoma cell line, CRL 1739. Western blot analysis was performed on CRL 1739 cultured in the presence of IL-4 (500 U/ml). Cells were lysed, protein extracted, and electroblotted; blots were then probed with murine monoclonal antibodies to specific intracellular proteins. Western blotting of CRL 1739 with antiphosphotyrosine antibody (4GlO) demonstrated multiple (140 kDa and 65 kDa) phosphoproteins seen only in IL-4-treated CRL 1739. Immunoprecipitation and blotting of CRL 1739 with specific secondary antibodies demonstrated that the 140 kDa phosphoprotein was IL-4Rα, the 6SkDa phosphoprotein was IL-ZRγc, the 130 kDa phosphoprotein was Janus kinase (JAK1), and the 116 kDa phosphoprotein was JAK3. Reverse transcription-polymerase chain reaction with specific primers demonstrated that multiple human gastric tumor specimens expressed IL-4Rα and IL-2Rγc but did not express the leukocyte marker CD45. These results suggest that human gastric carcinomas may express functional cytokine receptors, including the IL-2Rγc commonly found in association with the lymphocyte IL-2R. These receptors may represent novel targets for directing cytokine-based therapy.