Mk. Ganapathi et al., RESISTANCE TO INTERLEUKIN-6 IN HUMAN NONSMALL CELL LUNG-CARCINOMA CELL-LINES - ROLE OF RECEPTOR COMPONENTS, Cell growth & differentiation, 7(7), 1996, pp. 923-929
The role of interleukin 6 (IL-6) in regulating the growth of three hum
an non-small cell lung carcinoma (NSCLC) cell lines (NSCLC-3, NSCLC-B,
and NSCLC-7, derived from a primary lesion, a brain lesion, and lymph
node metastases, respectively) was examined. Although IL-6 alone did
not alter the growth of these cells, the addition of soluble IL-6 rece
ptor (sIL-6R) led to the inhibition of proliferation of one of the NSC
LC cell lines, NSCLC-5. This antiproliferative effect was neutralized
by antibodies to IL-6 and the IL-6R binding and signaling component (g
p130). The IL-6-related cytokines, leukemia inhibitory factor and onco
statin M, inhibited proliferation of NSCLC-B cells but were ineffectiv
e in NSCLC-3 and NSCLC-7 cells. NSCLC-7 cells (but not NSCLC-3 or NSCL
C-B cells) secreted biologically active IL-6 and expressed IL-6R. Howe
ver, antibodies to IL-6 or gp130 failed to alter the proliferation of
NSCLC-7 cells. All three cell lines expressed gp130 mRNA and protein.
The level of expression of gp130 protein varied in the three cell line
s (NSCLC-7 > NSCLC-3 > NSCLC-5). The examination of tyrosine phosphory
lation of gp130 (as an early event in IL-6 signal transduction) reveal
ed that gp130 could be phosphorylated in all cell lines after stimulat
ion with IL-6 and/or IL-6 + sIL-6R. These results demonstrate that the
mechanisms responsible for IL-6 resistance in different NSCLC cell li
nes vary and involve defects at either one or more levels of the IL-6
signaling cascade, In the NSCLC-5 cell line, IL-6 resistance (which ca
n be reversed in the presence of sIL-6R) is due to the transcriptional
inactivation of the IL-6R gene. In contrast, in the other two cell li
nes (NSCLC-3 and NSCLC-7), defect(s) in the signaling cascade downstre
am of gp130 phosphorylation, together with a lack of expression of IL-
6R in NSCLC-3 cells, result in IL-6 resistance.