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Volume 272, Number 48, Issue of November 28, 1997 pp. 30421-30428
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

A Sweat Gland-derived Differentiation Activity Acts through Known Cytokine Signaling Pathways

(Received for publication, May 16, 1997, and in revised form, September 16, 1997)

Beth A. Habecker ^§ , Aviva J. Symes ^** , Neil Stahl , Nicole J. Francis , Aris Economides , J. S. Fink , George D. Yancopoulos and Story C. Landis ^§

From the  Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106,  Molecular Neurobiology Laboratory, Massachusetts General Hospital, Boston, Massachusetts 02114,  Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591, ^§ Neural Development Section, NINDS, National Institutes of Health, Bethesda, Maryland 20892, and the ^** Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814

The sympathetic innervation of sweat glands undergoes a target-induced noradrenergic to cholinergic/peptidergic switch during development. Similar changes are induced in cultured sympathetic neurons by sweat gland cells or by one of the following cytokines: leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), or cardiotrophin-1 (CT-1). None of these is the sweat gland-derived differentiation activity. LIF, CNTF, and CT-1 act through the known receptors LIF receptor  (LIFR) and gp130 and well defined signaling pathways including receptor phosphorylation and STAT3 activation. Therefore, to determine whether the gland-derived differentiation activity was a member of the LIF/CNTF cytokine family, we tested whether it acted via these same receptors and signal cascades. Blockade of LIFR inhibited the sweat gland differentiation activity in neuron/gland co-cultures, and extracts of gland-containing footpads stimulated tyrosine phosphorylation of LIFR and gp130. An inhibitor (CGX) of molecules that bind the CNTFR, which is required for CNTF signaling, did not affect the gland-derived differentiation activity. Soluble footpad extracts induced the same changes in NBFL neuroblastoma cells as LIF and CNTF, including increased vasoactive intestinal peptide mRNA, STAT3 dimerization, and DNA binding, and stimulation of transcription from the vasoactive intestinal peptide cytokine-responsive element. Thus, the sweat gland-derived differentiation activity uses the same signaling pathway as the neuropoietic cytokines, and is likely to be a family member.

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