Studies of interleukin 16 biologic function.

摘要

Interleukin (IL)-16 is a cytokine cleaved by caspase-3 from a constitutively expressed precursor, pro-IL-16. The biological activities of IL-16 are induced by its interaction with CD4 expressed on responder cells including T cells, monocytes, eosinophils, dendritic cells and pro-B cells. In vitro bioactivities of IL-16 include chemotaxis, induction of IL-2 receptor expression, transient inhibition of T-cell antigen receptor signaling and inhibition of lentivirus replication. Tissue expression of IL-16 is seen in several human diseases including asthma, sarcoidosis, rheumatoid arthritis, Grave's disease and tuberculosis. The in vitro data and disease associations suggest that IL-16 might function as a pro-inflammatory or anti-inflammatory factor, but its actual role in the immune response in vivo remains unknown. To address this question the murine IL-16 gene was cloned and sequenced, and a mouse with targeted mutation of IL-16 was created. The IL-16 gene comprises seven exons separated by six introns over a span of 12 kilobases. The protein coding regions are contained in exons 2 through 7, and the caspase-3 cleavage site lies within exon 5. A targeting vector containing a mutated pro-IL-16 gene with a neo cassette replacing the sequences coding for the mature cytokine was used to generate IL-16−/− mice in the BALB/c and C57BL/6 backgrounds. IL-16 deficiency does not influence fertility and it is not associated with any gross anatomic pathology. There is no difference in leukocyte numbers or the expression of T-cell and B-cell markers between IL-16 −/− mice and wildtype littermates. In vitro activation studies comparing IL-16−/− and IL-16 +/+ lymphocytes produced suggestive evidence that IL-16 supports the viability of activated CD4+ T-cells, but this was not conclusively established. To reveal any stressed immune phenotype, IL-16−/− and +/+ mice were challenged by pulmonary infection with Cryptococcus neoformans. IL-16-deficient mice were highly susceptible to infection, failing to control replication of the yeast and developing progressive and diffuse pneumonitis. This study provides the first evidence that IL-16 is necessary for protective immunity, and lays the foundation for understanding its specific functions in the network of immune regulation.