DIFFERENTIAL-EFFECTS OF MACROPHAGE-COLONY-STIMULATING AND GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTORS ON CYTOKINE GENE-EXPRESSION DURING RAT ALVEOLAR MACROPHAGE DIFFERENTIATION INTO MULTINUCLEATED GIANT-CELLS (MGC) - ROLE FOR IL-6 IN TYPE-2 MGC FORMATION

Macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophag e (GM)-CSF stimulate the diiferentiation of rat alveolar macrophages ( AM) into multinucleated giant cells (MGC) with distinct phenotypes (ty pe 1 and type 2 MGC). In the present study, we analyzed the profile of cytokine gene expression induced respectively, by M-CSF and GM-CSF du ring rat AM differentiation using reverse transcription-PCR, Enhanced mRNA expression for IL-1 alpha; TNF-alpha, and TGF-beta(1) was observe d 3 h after treatment with M-CSF (50 U/ml) or GM-CSF (50 U/ml). In con trast, IL-6 mRNA expression was increased by GM-CSF but not M-CSF, Kin etic analysis indicated that CM-CSF stimulated IL-6 expression early ( 1.5 h), with maximal effect observed at 24 h and up to 5 days thereaft er. Increased mRNA levels for IL-6 were associated with higher IL-6 ac tivity in the culture media of differentiating AM. IL-6 activity was s timulated 3 h after treatment with CM-CSF and increased with time (up to 5 days). interestingly, addition of exogenous IL-6 (20-100 ng/ml) a lone or in combination with CM-CSF to AM cultures increased slightly a nd selectively the formation of MGC with type 2 phenotype. Conversely, neutralization of endogenous IL-G during AM differentiation into MCC inhibited significantly (up to 50%) the formation of type 2 MGC, these results suggest a role for IL-6 in the formation of type 2 MGC and pr ovide some insights into the mechanisms of MGC formation and the proce sses that regulate it positively.