Hypoxic preconditioning induces neuroprotective stanniocalcin-1 in brain via IL-6 signaling.
OBJECTIVE
Exposure of animals for a few hours to moderate hypoxia confers relative protection against subsequent ischemic brain damage. This phenomenon, known as hypoxic preconditioning, depends on new RNA and protein synthesis, but its molecular mechanisms are poorly understood. Increased expression of IL-6 is evident, particularly in the lungs of animals subjected to hypoxic preconditioning. Stanniocalcin-1 (STC-1) is a 56-kDa homodimeric glycoprotein originally discovered in bony fish, where it regulates calcium/phosphate homeostasis and protects against toxic hypercalcemia. We originally reported expression of mammalian STC-1 in brain neurons and showed that STC-1 guards neurons against hypercalcemic and hypoxic damage.


METHODS
We treated neural Paju cells with IL-6 and measured the induction of STC-1 mRNA. In addition, we quantified the effect of hypoxic preconditioning on Stc-1 mRNA levels in brains of wild-type and IL-6 deficient mice. Furthermore, we monitored the Stc-1 response in brains of wild-type and transgenic mice, overexpressing IL-6 in the astroglia, before and after induced brain injury.


RESULTS
Hypoxic preconditioning induced an upregulated expression of Stc-1 in brains of wild-type but not of IL-6-deficient mice. Induced brain injury elicited a stronger STC-1 response in brains of transgenic mice, with targeted astroglial IL-6 expression, than in brains of wild-type mice. Moreover, IL-6 induced STC-1 expression via MAPK signaling in neural Paju cells.


CONCLUSIONS
These findings indicate that IL-6-mediated expression of STC-1 is one molecular mechanism of hypoxic preconditioning-induced tolerance to brain ischemia.
Westberg
Johan A
JA
Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland.
Serlachius
Martina
M
Lankila
Petri
P
Penkowa
Milena
M
Hidalgo
Juan
J
Andersson
Leif C
LC
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019194:Ischemic Preconditioning / Q000379:methods*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology
D006023:Glycoproteins; D015850:Interleukin-6; D018696:Neuroprotective Agents; C051795:teleocalcin