REGULATION OF INTERLEUKIN-1 RECEPTOR ANTAGONIST BY TH1 AND TH2 CYTOKINES

Airway inflammation is an important aspect of asthma. Recent studies o f airway inflammation in asthma have focused attention on cytokines re leased by T helper lymphocyte type 1 (Th1)- and Th2-Like T cells. Inte rleukin (IL)-1 is also increased in the airways of asthmatics, and it is most likely derived from airway and alveolar macrophages. The effec ts of Th1 or Th2 cytokines on the release of IL-1 or its specific anta gonist, IL-1ra, have not been well studied. We examined the response o f THP-1 cells, a myelomonocytic cell line, to stimulation with various Th1 and Th2 cytokines and found that IL-4, IL-10, and IFN-gamma incre ased IL-1ra mRNA and protein release. The increase in mRNA was not due to an increase in IL-1ra mRNA stability. IL-4 (10 ng/ml) increased IL -1ra release from 9,641 +/- 322 [from cells stimulated with lipopolysa ccharide (LPS) alone] to 50,796 +/- 1,917 pg/ml (from cells stimulated with LPS and IL-4). IL-10 (10 ng/ml) caused a similar upregulation of IL-1ra from LPS-stimulated cells: 87,478 +/- 7,808 compared with 8,00 4 +/- 1,166 pg/ml released from the cells stimulated with LPS alone. C ells stimulated with IFN-gamma (100 U/ml) and LPS released 27,854 +/- 3,626 pg/ml of IL-1ra, compared with 9,069 +/- 236 pg/ml in the presen ce of LPS alone. In addition, the Th1 cytokine, IFN-gamma, but not the Th2 cytokines, IL-4 and IL-10, upregulated IL-1 beta mRNA and increas ed the release of IL-1 beta protein. Similar studies were performed us ing freshly isolated monocytes. These data suggest that the Th2 cytoki nes, IL-4 and IL-10, may cause an overall reduction of IL-1 activity. The findings may be relevant to the inflammatory response of asthma.