Intracellular interaction of interleukin-15 with its receptor alpha during production leads to mutual stabilization and increased bioactivity.
We show that co-expression of interleukin 15 (IL-15) and IL-15 receptor alpha (IL-15Ralpha) in the same cell allows for the intracellular interaction of the two proteins early after translation, resulting in increased stability and secretion of both molecules as a complex. In the absence of co-expressed IL-15Ralpha, a large portion of the produced IL-15 is rapidly degraded immediately after synthesis. Co-injection into mice of IL-15 and IL-15Ralpha expression plasmids led to significantly increased levels of the cytokine in serum as well as increased biological activity of IL-15. Examination of natural killer cells and T lymphocytes in mouse organs showed a great expansion of both cell types in the lung, liver, and spleen. The presence of IL-15Ralpha also increased the number of CD44(high) memory cells with effector phenotype (CD44(high)CD62L-). Thus, mutual stabilization of IL-15 and IL-15Ralpha leads to remarkable increases in production, stability, and tissue availability of bioactive IL-15 in vivo. The in vivo data show that the most potent form of IL-15 is as part of a complex with its receptor alpha either on the surface of the producing cells or as a soluble extracellular complex. These results explain the reason for coordinate expression of IL-15 and IL-15Ralpha in the same cell and suggest that the IL-15Ralpha is part of the active IL-15 cytokine rather than part of the receptor.
Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, NCI-Frederick, National Instsitutes of Health, MD 21702-1201, USA.
Cristina
C
Bergamaschi
Margherita
M
Rosati
Rashmi
R
Jalah
Antonio
A
Valentin
Viraj
V
Kulkarni
Candido
C
Alicea
Gen-Mu
GM
Zhang
Vainav
V
Patel
Barbara K
BK
Felber
George N
GN
Pavlakis
D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D019409:Interleukin-15 / Q000097:blood / Q000378:metabolism*; D053720:Interleukin-15 Receptor alpha Subunit / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D011485:Protein Binding; D013154:Spleen / Q000378:metabolism
D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit