Induction of cell cycle arrest and B cell terminal differentiation by CDK inhibitor p18(INK4c) and IL-6

Immunity. 1997 Jan;6(1):47-56. doi: 10.1016/s1074-7613(00)80241-1.

Abstract

Cell cycle arrest and cell death are tightly coupled to terminal differentiation of B cells to plasma cells in vivo. This process was recapitulated in vitro by stimulation of IgG-bearing human B lymphoblastoid cells with interleukin-6 (IL-6), which led to orderly cell cycle arrest, differentiation, and apoptosis. In terminally differentiated plasmacytoid cells, phosphorylation of pRb was suppressed, correlating with the activation of the D-type cyclin-dependent kinase (CDK) inhibitors p18(INK4c) and p21(WAF1/CIP1). The expression of CDK6, however, remained unchanged. Activation of p18 by IL-6 was rapid, concomitant with marked enhancement of its association with CDK6 and cell cycle arrest. Overexpression of p18 in IgM-bearing lymphoblastoid cells, which differentiated in response to IL-6 but did not exit the cell cycle, reconstituted coupled differentiation and cell cycle arrest. Thus, CDK inhibitors, in particular p18, are likely to play a pivotal role in controlling cell cycle arrest and cell death in terminal differentiation of late-stage B cells to plasma cells via inhibition of pRb phosphorylation by CDK6.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis
  • B-Lymphocytes / cytology*
  • Carrier Proteins / physiology*
  • Cell Cycle Proteins*
  • Cell Cycle*
  • Cell Differentiation*
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinase Inhibitor p18
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases*
  • Cyclins / metabolism
  • Enzyme Inhibitors*
  • HLA-D Antigens / metabolism
  • Humans
  • Immunoglobulin G / metabolism
  • Interleukin-6 / physiology*
  • Phosphorylation
  • Plasma Cells / cytology*
  • Protein Binding
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Retinoblastoma Protein / metabolism
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins*

Substances

  • CDKN1A protein, human
  • CDKN2C protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p18
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • HLA-D Antigens
  • Immunoglobulin G
  • Interleukin-6
  • Retinoblastoma Protein
  • Tumor Suppressor Proteins
  • Protein-Serine-Threonine Kinases
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinases