title: The role of CD4-dependent signaling in interleukin-16 induced c-Fos expression and facilitation of neurite outgrowth in cerebellar granule neurons.
abstract: Neuronal interleukin 16 (NIL-16) is the larger neural-specific splice variant of the interleukin-16 (IL16) gene and shows restricted expression to post-mitotic neurons of the mammalian hippocampus and cerebellum. Although the N-terminus of NIL-16 is unique to the neuronal variant, the C-terminus is identical to pro-IL-16, the IL-16 precursor expressed primarily in T-cells. IL-16 was originally described as a proinflammatory cytokine and has diverse immunoregulatory effects which involve signaling through CD4. NIL-16-expressing neurons can secrete IL-16 and may express CD4; moreover, treatment of cultured cerebellar granule neurons (CGCs) with IL-16 increases the expression of c-Fos, an immediate-early gene which transcriptionally regulates genes directing survival, proliferation, and growth. Taken together, we hypothesize that IL-16 functions as a neuroregulatory cytokine which signals through neuronal CD4 receptors. In this study, we investigated the role of CD4 in IL-16-induced c-Fos expression in CGCs, as well as the effects of IL-16 on neuronal survival and growth. We detected components involved in IL-16-signaling in lymphocytes, including CD4 and the associated tyrosine kinase p56(lck), in CGCs using qRT-PCR and immunoblotting. We also show that IL-16 induces c-Fos expression in wild-type CGCs, but not CD4-deficient CGCs or following inhibition of p56(lck). Finally, treatment of CGCs with IL-16 enhanced neurite outgrowth, an effect also observed in CD4-deficient CGCs. Taken together, our results indicate that IL-16-signaling affects neuronal gene expression and growth through CD4-dependent and independent pathways.
authors.affiliation: The College of Wooster, 931 College Avenue, Wooster, OH 44691, USA. cfenster@wooster.edu
authors.forename: Catherine P
authors.initials: CP
authors.lastname: Fenster
authors.forename: Hope K
authors.initials: HK
authors.lastname: Chisnell
authors.forename: Carl R
authors.initials: CR
authors.lastname: Fry
authors.forename: Steven D
authors.initials: SD
authors.lastname: Fenster
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D016762:Genes, fos / Q000235:genetics*; D019410:Interleukin-16 / Q000494:pharmacology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D015704:CD4 Antigens; D019410:Interleukin-16; D012313:RNA; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)