A potent human interleukin-4 antagonist stimulates the proliferation of murine cells expressing the human interleukin-4 binding chain.
A single-amino-acid substitution mutant form of human interleukin-4 (hIL-4), Y124D.hIL-4, has been described previously as an antagonist of the effects of hIL-4 on various human cells. The murine T-cell leukemic cell line CT.h4S, which expresses the human IL-4 receptor, proliferates in response to both hIL-4 and murine IL-4. Although Y124D.hIL-4 antagonizes the proliferative effects of hIL-4 on human phytohaemagglutinin-stimulated peripheral blood mononuclear cells, Y124D.hIL-4 is a potent stimulator for CT.h4S cells. Molecular modelling studies were performed to investigate the stability of different conformations of residue 124 as well as the efficiency of different molecular mechanics force fields in homology modelling. We suggest that the aspartate substitution alters the C-terminal end of the D-helix in such way that the analogue still binds to the human IL-4 receptor alpha-chain and signals through the murine gamma c-chain. In contrast, the Y124D.hIL-4/IL-4 receptor complex cannot signal through the human gamma c-chain.
Davis
I D
ID
Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Royal Melbourne Hospital, Victoria, Australia.
Treutlein
H R
HR
Friedrich
K
K
Burgess
A W
AW
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D002455:Cell Division; D003196:Computer Graphics; D018360:Crystallography, X-Ray; D006801:Humans; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015461:Leukemia, Prolymphocytic, T-Cell / Q000378:metabolism / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008213:Lymphocyte Activation; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010835:Phytohemagglutinins / Q000494:pharmacology; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D018123:Receptors, Interleukin / Q000737:chemistry / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014867:Water
D000911:Antibodies, Monoclonal; D010835:Phytohemagglutinins; D018123:Receptors, Interleukin; D014867:Water; D015847:Interleukin-4