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Neurotrophic Actions of PACAP-38 and LIF on Human Neuroblastoma SH-SY5Y Cells

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Abstract

The neurotrophic actions of pituitary adenylate cyclase-activating polypeptide (PACAP)-38 and leukemia inhibitory factor (LIF) were investigated in human neuroblastoma SH-SY5Y cells. Effects on differentiation were assessed through monitoring morphological changes and Western blot analysis of the expression of neuronal marker proteins. In contrast to PACAP-38, which induced a 5.5-fold increase in the number of neurite-bearing cells, LIF had no significant effect on cell morphology compared to control cells over the 4-day time course. Cells co-treated with PACAP-38+LIF showed a similar increase in neurite-bearing cells compared to those treated with PACAP-38 alone. Cell morphology was similar for PACAP-38-treated and PACAP-38+LIF-co-treated cells, with the formation of bipolar neuron-like cells with long thin neurites, topped by growth cone-like structures and varicosities. SH-SY5Y cells express tyrosine hydroxylase (TH) but only low levels of the neuronal marker proteins: Bcl-2, GAP-43 and choline acetyltransferase (ChAT). Treatment of cells with PACAP-38 induced the expression of Bcl-2, GAP-43, and ChAT but did not appear to alter the expression of TH. LIF failed to induce the expression of GAP-43 and had little effect on the expression of TH, but did induce the expression of Bcl-2 and upregulated the expression of ChAT. Co-treatment with LIF had no effect on PACAP-38-induced expression of Bcl-2, GAP-43, and ChAT. Cells differentiated for 4 days with PACAP-38 or treated with LIF also displayed increased resistance to hypoxic conditions and to treatment with H2O2 and TNFα. The increased resistance to hypoxic conditions for PACAP-differentiated cells was blocked by the p38 MAP kinase inhibitor, SB203580, but not by the MEK1 inhibitor, PD98059. Additionally, cell proliferation assays show that LIF, but not PACAP-38, stimulates proliferation of SH-SY5Y cells, and this observed increase by LIF is not attenuated by co-treatment with PACAP. Further investigation of the intracellular signaling pathways mediating the neurotrophic effects of PACAP on SH-SY5Y cells indicate that neither phospholipase C activation nor Ca2+/calmodulin-dependent kinase II (CAMKII) are involved.

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Abbreviations

PACAP:

pituitary adenylate cyclase-activating polypeptide

VIP:

vasoactive intestinal peptide

LIF:

leukemia inhibitory factor

PAC1 :

PACAP receptor type I

VPAC1 :

VIP/PACAP receptor type I

VPAC2 :

VIP/PACAP receptor type 2

GPCR:

G protein-coupled receptor

AC:

adenylate cyclase

Epac:

exchange protein directly activated by cAMP

PKA:

cAMP-dependent protein kinase A

ERK:

extracellular signal-regulated kinase

PLC:

phospholipase C

InsP:

inositol phosphates

RA:

retinoic acid

CaMKII:

Ca2+/calmodulin-dependent protein kinase II

GAP-43:

growth-associated protein-43

ChAT:

choline acetyltransferase

TH:

tyrosine hydroxylase

STAT:

signal transducer and activator of transcription

PKB/Akt:

protein kinase B

PI3-K:

phosphatidylinositol-3-kinase

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

NGF:

nerve growth factor

BDNF:

brain-derived neurotrophic factor

LPS:

lipopolysaccharide

AIP:

autocamtide-2-related inhibitory peptide

ES:

embryonic stem cell

FBS:

fetal bovine serum

RT-PCR:

reverse transcriptase polymerase chain reaction

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Acknowledgments

We wish to thank Dr Clett Erridge for the gifts of TNFα and LPS and Mr. Alex McDowall for the use of his anaerobic chamber. We also would like to acknowledge the influential work of Professor Akira Arimura on this research, particularly his discovery and characterization of PACAP as well as his inspiration, encouragement, and generosity to others that have led towards a much greater understanding of its biological functions. This research was supported by the Wellcome Trust.

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  1. Strathclyde Institute of Pharmacy and Biomedical Sciences, Royal College, 204 George Street, Glasgow, G1 1XW, UK

    T. K. Monaghan, C. Pou, C. J. MacKenzie, R. Plevin & E. M. Lutz

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  1. T. K. Monaghan
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  2. C. Pou
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  3. C. J. MacKenzie
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Monaghan, T.K., Pou, C., MacKenzie, C.J. et al. Neurotrophic Actions of PACAP-38 and LIF on Human Neuroblastoma SH-SY5Y Cells. J Mol Neurosci 36, 45–56 (2008). https://doi.org/10.1007/s12031-008-9082-6

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