C-C CHEMOKINES DIFFERENTIALLY ALTER INTERLEUKIN-4 PRODUCTION FROM LYMPHOCYTES

The expression of cytokines can dictate the intensity, chronicity, and type of immune/inflammatory response that is produced. These events m ay be regulated by accumulation of particular cell populations at a si te of immune response that can be regulated by the expression of speci fic chemokines. Recent data have indicated that chemokines also have d irect effects on cellular activation. In particular, T lymphocyte resp onses have been divided into two distinct phenotypes, designated by TH 1- and TH2-type cytokine expression. Although it is recognized that di vergent T-lymphocyte-derived cytokine phenotypes exist, the mechanisms that dictate the expression of these cytokines and ultimately the div ision of these immune responses is not entirely clear. In the present study, we present data that the C-C chemokine family members may be a factor influencing the direction of T-cell-derived lymphokine producti on. To elucidate the role of C-C chemokines, MIP-1 alpha and MCP-1, we have used both antigen-specific (schistosomal egg antigen (SEA)) and nonspecific (conconavalin (Con) A) stimuli. Using TH2-type lymphocyte populations from SEA-sensitized mice, a significant increase in IL-4 m RNA expression and protein production was observed when MCP-1 was adde d to the culture. Conversely, MIP-1 alpha treatment appeared to decrea se interleukin (IL)-4 production. Interestingly, the proliferative res ponse in the TH2-type (SEA-specific) response was up-regulated by MIP- 1 alpha whereas MCP-1 down-regulated the response, inversely correlati ng with IL-4 production. Primary stimulation of naive lymphocytes with Con A induces a predominant interferon (IFN)-gamma response, whereas the second stimulation of the same lymphocytes with Con A induces both IFN-gamma and IL-4. When the two C-C chemokines were individually co- incubated with Con-A-stimulated lymphocytes, both up-regulated IFN-gam ma production and proliferation during the primary stimulation. Simila rly, in the secondary response, both chemokines further upregulated IF N-gamma production; however, only MCP-1 co-stimulation increased IL-4 production, whereas MIP-1 alpha significantly decreased IL-4 productio n in these same cell populations. These results were also reflected in steady-state levels of mRNA expression. These results suggest that th e production of C-C chemokines (MCP-1 or MIP-1 alpha) during an immune response may aid in determining the type of cytokines produced and th e level of lymphocyte activation during a particular response.