Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 116, Issue 2, Pages 447-455Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI26523
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- NIAID NIH HHS [R21 AI063515] Funding Source: Medline
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Recent evidence has indicated that leptin, an adipocyte-secreted hormone belonging to the helical cytokine family, significantly influences immune and autoimmune responses. We investigate here the mechanisms by which in vivo abrogation of leptin effects protects SJL/J mice from proteolipid protein peptide PLP139-151-induced EAE, an animal model of MS. Blockade of leptin with and-leptin Abs or with a soluble mouse leptin receptor chimera (ObR:Fc), either before or after onset of EAE, improved clinical score, slowed disease progression, reduced disease relapses, inhibited PLP139-151-specific T cell proliferation, and switched cytokine secretion toward a Th2/regulatory profile. This was also confirmed by induction of forkhead box p3 (Foxp3) expression in CD4(+) T cells in leptin-neutralized mice. Importantly, anti-leptin treatment induced a failure to downmodulate the cyclin-dependent kinase inhibitor p27 (p27(Kip-1)) in autoreactive CD4(+) T cells. These effects were associated with increased tyrosine phosphorylation of both ERK1/2 and STAT6. Taken together, our data provide what we believe is a new molecular basis for leptin antagonism in EAE and envision novel strategies of leptin-based molecular targeting in the disease.
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