Role of endogenous tumor necrosis factor alpha and interleukin 1 for experimental tumor growth and the development of cancer cachexia.
The aim of this study was to evaluate to what extent tumor necrosis factor alpha (TNF-alpha) and interleukin 1 may explain the development of experimental cancer cachexia. For this purpose, C57BL/6J mice bearing a transplantable low differentiated rapidly growing tumor were passively immunized every other day with rabbit or rat neutralizing immunoglobulins against either TNF-alpha (anti-TNF) or against an interleukin 1 receptor (anti-IL-1r). Anti-IL-1r in itself had no agonistic effect to the type I, T-cell/fibroblast IL-receptor. Tumor-bearing mice receiving either preimmune antiserum or nonimmune rat hybridoma IgG served as controls. Anti-TNF and anti-IL-1r inhibited tumor growth significantly, as measured by a lower wet and dry tumor weight at the end of 11 days of antiserum treatment (P less than 0.05). The acute phase response in tumor-bearing animals, measured as an increase in liver weight, hepatic RNA content, and increases in plasma concentrations of circulating IL-6, serum amyloid P, transferrin, complement (C3), and a decrease in plasma albumin, were unaffected by the specific antiserum treatments. Food intake, which declined significantly in pre/nonimmune injected tumor-bearing controls, was significantly improved in tumor-bearing animals immunized against TNF-alpha or the IL-1r. Whole body lipid content showed a trend to improvement in specifically immunized animals (P less than 0.07). The effects on whole body fat-free dry weight were insignificant, although numerically higher in specifically immunized tumor-bearing animals. The combination of anti-TNF and anti-IL-1r antiserum had no additive effects compared to single antiserum treatment suggesting that the two antibody treatments acted through a common mechanism. Cultured tumor cells, established from growing tumors, were sensitive to anti-TNF and anti-IL-1r, which both reduced tumor growth in vitro. This inhibitory effect by the antiserum could in part be reversed by the addition of recombinant IL-1 alpha and TNF alpha. We conclude that both TNF and IL-1 are involved in tumor growth and thus the progression of cancer cachexia. It seems as if the role of TNF and IL-1 was to promote tumor growth rather than restrict tumor growth in the present model. In this sense both TNF and IL-1 may act as tumor growth factors.
Department of Surgery, Sahlgrenska Hospital, Gothenburg, Sweden.
J
J
Gelin
L L
LL
Moldawer
C
C
Lönnroth
B
B
Sherry
R
R
Chizzonite
K
K
Lundholm
D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D001823:Body Composition; D002100:Cachexia / Q000503:physiopathology*; D002478:Cells, Cultured; D005247:Feeding Behavior / Q000502:physiology; D005260:Female; D007158:Immunologic Techniques; D007375:Interleukin-1 / Q000502:physiology*; D015850:Interleukin-6 / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000473:pathology / Q000503:physiopathology*; D011971:Receptors, Immunologic / Q000502:physiology; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000209:Acute-Phase Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha