Cross-talk among gp130 cytokines in adipocytes.
The interleukin-6 (IL-6) family of cytokines is a family of structurally and functionally related proteins, including IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1). These proteins are also known as gp130 cytokines because they all share gp130 as a common transducer protein within their functional receptor complexes. Several of these cytokines (LIF, OSM, CNTF, and CT-1) also utilize the LIF receptor (LIFR) as a component of their receptor complex. We have shown that all of these cytokines are capable of activating both the JAK/STAT and p42/44 mitogen-activated protein kinase signaling pathways in 3T3-L1 adipocytes. By performing a variety of preincubation studies and examining the ability of these cytokines to activate STATs, ERKs, and induce transcription of SOCS-3 mRNA, we have also examined the ability of gp130 cytokines to modulate the action of their family members. Our results indicate that a subset of gp130 cytokines, in particular CT-1, LIF, and OSM, has the ability to impair subsequent signaling activity initiated by gp130 cytokines. However, IL-6 and CNTF do not exhibit this cross-talk ability. Moreover, our results indicate that the cross-talk among gp130 cytokines is mediated by the ability of these cytokines to induce ligand-dependent degradation of the LIFR, in a proteasome-independent manner, which coincides with decreased levels of LIFR at the plasma membrane. In summary, our results demonstrate that an inhibitory cross-talk among specific gp130 cytokines in 3T3-L1 adipocytes occurs as a result of specific degradation of LIFR via a lysosome-mediated pathway.
Zvonic
Sanjin
S
Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803, USA.
Baugh
James E
JE
Arbour-Reily
Patricia
P
Mynatt
Randall L
RL
Stephens
Jacqueline M
JM
D017667:Adipocytes / Q000502:physiology*; D018929:Cell Culture Techniques; D002462:Cell Membrane / Q000502:physiology; D050822:Cytokine Receptor gp130 / Q000502:physiology*; D016207:Cytokines / Q000502:physiology*; D006801:Humans; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008024:Ligands; D008247:Lysosomes; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger; D020239:Receptor Cross-Talk / Q000502:physiology*; D018121:Receptors, Cytokine / Q000378:metabolism*; D053606:Receptors, OSM-LIF; D014158:Transcription, Genetic
D016207:Cytokines; C507840:LIFR protein, human; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008024:Ligands; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D050822:Cytokine Receptor gp130; D046988:Proteasome Endopeptidase Complex