Cytokines and soluble cytokine receptor induction after IL-12 administration in cancer patients.
This study shows that subcutaneous administration of increasing doses of IL-12, once a week, in 21 cancer patients increased the expression of cytokine genes (interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), IP-10, MIG, IL-10, IL-4) in peripheral blood mononuclear cells even at very low doses (30 ng/kg). Surprisingly, no circulating TNF-alpha or IL-4 could be detected in the plasma of patients treated with IL-12. However, a marked increase of soluble IL-4 receptor was demonstrated in the plasma of five of the six patients studied, which may represent an additional mechanism by which IL-12 inhibits the development of the Th2 response in vivo. A marked decline of IFN-gamma and IP10 induction was recorded after repeated cycles of IL-12. In contrast, in most patients IL-12 increased IL-10 expression with no subsequent decrease during the course of therapy, and even an earlier peak of IL-10 induction at the 6th cycle. In addition, a constant up-regulation of serum soluble IFN-gamma receptor levels was observed after each cycle of IL-12 treatment with a delayed peak compared with the IFN-gamma peak. The constant rise of IL-10 and soluble IFN-gamma receptor during IL-12 therapy may therefore contribute to the inhibition of IFN-gamma activity detected after repeated cycles of IL-12. Lastly, a marked heterogeneity of cytokine induction was observed from one patient to another, which appeared to be independent of the dose of IL-12 administered. These data may lead to a better understanding of the biological activity of IL-12 and the in vivo mechanisms of its regulation.
Haicheur
N
N
Unité d'Immunologie Clinique, INSERM 255, Institut Curie, Paris.
Escudier
B
B
Dorval
T
T
Negrier
S
S
De Mulder
P H
PH
Dupuy
J M
JM
Novick
D
D
Guillot
T
T
Wolf
S
S
Pouillart
P
P
Fridman
W H
WH
Tartour
E
E
D000970:Antineoplastic Agents / Q000097:blood; D001483:Base Sequence; D054370:Chemokine CXCL9; D018925:Chemokines / Q000097:blood / Q000235:genetics; D019743:Chemokines, CXC / Q000097:blood / Q000235:genetics; D016207:Cytokines / Q000097:blood* / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics; D018664:Interleukin-12 / Q000008:administration & dosage / Q000627:therapeutic use*; D015847:Interleukin-4 / Q000097:blood / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics; D018121:Receptors, Cytokine / Q000097:blood* / Q000235:genetics; D019948:Receptors, Interleukin-4 / Q000097:blood / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012995:Solubility; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; C080810:CXCL9 protein, human; D054370:Chemokine CXCL9; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma