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. 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 beta (LIFRbeta) 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 LIFRbeta inhibited the sweat gland differentiation activity in neuron/gland co-cultures, and extracts of gland-containing footpads stimulated tyrosine phosphorylation of LIFRbeta and gp130. An inhibitor (CGX) of molecules that bind the CNTFRalpha, 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.
Habecker
B A
BA
Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Symes
A J
AJ
Stahl
N
N
Francis
N J
NJ
Economides
A
A
Fink
J S
JS
Yancopoulos
G D
GD
Landis
S C
SC
D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D002454:Cell Differentiation; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D008562:Membrane Glycoproteins / Q000502:physiology; D009474:Neurons / Q000502:physiology; D053683:Oncostatin M; D010455:Peptides / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D020801:Receptor, Ciliary Neurotrophic Factor; D018121:Receptors, Cytokine / Q000502:physiology; D017475:Receptors, Nerve Growth Factor / Q000502:physiology; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D017783:Superior Cervical Ganglion / Q000166:cytology; D013545:Sweat Glands / Q000166:cytology* / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology; D014158:Transcription, Genetic; D014660:Vasoactive Intestinal Peptide / Q000235:genetics
D015703:Antigens, CD; D016207:Cytokines; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; C494201:Il6st protein, rat; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507842:Lifr protein, rat; D008222:Lymphokines; D008562:Membrane Glycoproteins; D010455:Peptides; D012333:RNA, Messenger; D020801:Receptor, Ciliary Neurotrophic Factor; D018121:Receptors, Cytokine; D017475:Receptors, Nerve Growth Factor; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D053683:Oncostatin M; D050822:Cytokine Receptor gp130; D014660:Vasoactive Intestinal Peptide; D020794:Receptor Protein-Tyrosine Kinases