Abstract TP271: Leukemia Inhibitory Factor Differentially Regulates Its Receptor in the Brain and Immune System After Stroke

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Abstract

Objective: To identify how leukemia inhibitory factor (LIF) regulates antioxidant neuroprotective and anti-inflammatory signaling through the expression and trafficking of its receptor (LIFR).

Hypothesis: LIF treatment after stroke confers neuroprotection by increasing protein expression and membrane localization of LIFR in neural cells and splenocytes.

Methods: Genomatix software was used to identify binding sites for the LIF-dependent transcription factors specificity protein 1 (Sp1) and myeloid zinc finger-1 (MZF-1) in the LIFR promoter. Male Sprague-Dawley rats underwent middle cerebral artery occlusion or sham surgery and injected with PBS or LIF (125 μg/kg) (n=8 per group) at 6, 24 and 48 h post-MCAO. Levels of LIFR, MZF-1, and Sp1 were measured using western blotting. Immunohistochemistry was used to determine localization of Sp1, LIF receptor, MZF-1, and superoxide dismutase 3, a LIF-inducible enzyme.

Results: LIF (1.494 OD ± 0.161) significantly increased brain LIFR levels in ipsilateral tissue at 72 h after stroke compared to sham surgery (0.299 OD ± 0.060) and PBS treatment (0.399 OD ± 0.154) (0.0281 OD ± 0.011, p<0.01). Splenic LIFR levels decreased significantly after LIF (0.170 OD ± 0.010) treatment compared to PBS (0.228 OD ± 0.285, p<0.05) and sham rats (0.329 OD ± 0.031, P<0.001). LIFR was localized to neuronal nuclei but translocated to the cell membrane after injury. After LIF treatment, MZF-1 and Sp1 co-localized with superoxide dismutase 3 in cortical neurons. LIF significantly increased MZF-1, but not Sp1, in spleen tissue (0.158 OD ± 0.038) compared to PBS (0.109 OD ± 0.044) and sham (0.090 OD ± 0.018).

Conclusions: Injury increases membrane localization of LIFR in neurons while LIF increases its receptor’s expression and Sp1/MZF-1 in stroke-injured neurons. As a part of its anti-inflammatory action, LIF causes downregulation of LIFR in the spleen after stroke.

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