Interferon-gamma-inducible protein (IP)-10 mRNA stabilized by RNA-binding proteins in monocytes treated with S100b.
Chemokines mediate the recruitment and activation of blood monocyte/macrophages and lymphocytes to sites of inflammation. Expression of the chemokine IP-10 (interferon-gamma-inducible protein) has been documented in several inflammatory and autoimmune disorders including type 1 diabetes. However, the mechanism of its expression in monocytes or its functional role in diabetes is not known. Advanced glycation end products acting via their receptor, RAGE, play major roles in diabetic complications. In this study, we observed for the first time that S100b, an inflammatory protein as well as a specific RAGE ligand, significantly increased IP-10 mRNA and protein levels in THP-1 monocytes as well as peripheral blood monocytes. Promoter luciferase assays showed that IP-10 mRNA accumulation by S100b was not via increased transcription. On the other hand, S100b significantly increased IP-10 mRNA half-life and stability. This appeared to be mediated by S100b-induced binding of specific RNA-binding protein(s) to a 3'-untranslated region-responsive region of the IP-10 mRNA. Our results demonstrate for the first time that diabetic stimuli such as RAGE ligands can induce inflammatory gene expression in monocytes via increased message stability.
Shanmugam
Narkunaraja
N
Gonda Diabetes Research Center, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Ransohoff
Richard M
RM
Natarajan
Rama
R
D020413:3' Untranslated Regions; D002467:Cell Nucleus / Q000378:metabolism; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000378:metabolism / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D009000:Monocytes / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism*
D020413:3' Untranslated Regions; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D017127:Glycation End Products, Advanced; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human