A SWEAT GLAND-DERIVED DIFFERENTIATION ACTIVITY ACTS THROUGH KNOWN CYTOKINE SIGNALING PATHWAYS

The sympathetic innervation of sweat glands undergoes a target-induced noradrenergic to cholinergic/peptidergic switch during development. S imilar changes are induced in cultured sympathetic neurons by sweat gl and cells or by one of the following cytokines: leukemia inhibitory fa ctor (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 bet a (LIFR beta) 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 th e LIF/CNTF cytokine family, we tested whether it acted via these same receptors and signal cascades. Blockade of LIFR beta inhibited the swe at gland differentiation activity in neuron/gland co-cultures, and ext racts of gland containing footpads stimulated tyrosine phosphorylation of LIFR beta and gp130, An inhibitor (CGX) of molecules that bind the CNTFR alpha, which is required for CNTF signaling, did not affect the gland derived differentiation activity. Soluble footpad extracts indu ced the same changes In NBFL neuroblastoma cells as LIF and CNTF, incl uding increased vasoactive intestinal peptide mRNA, STAT3 dimerization , and DNA binding, and stimulation of transcription from the vasoactiv e intestinal peptide cytokine-responsive element. Thus, the sweat glan d-derived differentiation activity uses the same signaling pathway as the neuropoietic cytokines, and is likely to be a family member.