Pro-IL-16 regulation in activated murine CD4+ lymphocytes.
Prior DNA microarray studies suggested that IL-16 mRNA levels decrease following T cell activation, a property unique among cytokines. We examined pro-IL-16 mRNA and protein expression in resting and anti-CD3 mAb-activated primary murine CD4(+) T cells. Consistent with the microarray reports, pro-IL-16 mRNA levels fell within 4 h of activation, and this response is inhibited by cyclosporin A. Total cellular pro-IL-16 protein also fell, reaching a nadir at 48 h. Pro-IL-16 comprises a C-terminal cytokine domain and an N-terminal prodomain that are cleaved by caspase-3. Pro-IL-16 expressed in transfected tumor cells was previously shown to translocate to the nucleus and to promote G(0)/G(1) arrest by stabilizing the cyclin-dependent kinase inhibitor p27(Kip1). In the present study, we observed increased S-phase kinase-associated protein 2 mRNA expression in IL-16 null mice, but basal expression and activation-dependent regulation of p27(Kip1) were no different from wild-type mice. Stimulation with anti-CD3 mAb induced transiently greater thymidine incorporation in IL-16-deficient CD4(+) T cells than wild-type controls, but there was no difference in cell survival or in the CFSE dilution profiles. Analysis of CD4(+) T cell proliferation in vivo using BrdU labeling similarly failed to identify a hyperproliferative phenotype in T cells lacking IL-16. These data demonstrate that pro-IL-16 mRNA and protein expression are dynamically regulated during CD4(+) T cell activation by a calcineurin-dependent mechanism, and that pro-IL-16 might influence T cell cycle regulation, although not in a dominant manner.
Ren
Fucheng
F
Division of Pulmonary and Critical Care Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Zhan
Xin
X
Martens
Gregory
G
Lee
Jinhee
J
Center
David
D
Hanson
Sue Kim
SK
Kornfeld
Hardy
H
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D019703:Calcineurin / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D019410:Interleukin-16 / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011498:Protein Precursors / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology; D014162:Transfection
D019410:Interleukin-16; D011498:Protein Precursors; D012333:RNA, Messenger; D019703:Calcineurin