IDENTIFICATION OF FUNCTIONAL DOMAINS ON HUMAN INTERLEUKIN-10

Interleukin 10 (IL-10) is a recently described natural endogenous immu nosuppressive cytokine that has been identified in human, murine, and other organisms, Human IL-10 (hIL-10) has high homology with murine IL -10 (mIL-10) as well as with an Epstein-Barr virus genome product BCRF I, This viral IL-10 (vIL-10) shares a number of activities with hIL-10 , IL-10 significantly affects chemokine biology, because human IL-10 i nhibits chemokine production and is a specific chemotactic factor for CD8+ T cells. It suppresses the ability of CD4+ T cells, but not CD8T cells, to migrate in response to IL-8, A nonapeptide (IT9302) with c omplete homology to a sequence of hIL-10 located in the C-terminal por tion (residues 152-160) of the cytokine was found to possess activitie s that mimic some of those of hIL-10. These are: (i) inhibition of IL- 1 beta-induced IL-8 production by peripheral blood mononuclear cell, ( ii) inhibition of spontaneous IL-8 production by cultured human monocy tes, (iii) induction of IL-1 receptor antagonistic protein production by human monocytes, (iv) induction of chemotactic migration of CD8+ hu man T lymphocytes in vitro, (v) desensitization of human CD8+ T cells resulting in an unresponsiveness toward rhIL-10-induced chemotaxis, (v i) suppression of the chemotactic response of CD4+ T human lymphocytes toward IL-8, (vii) induction of IL-4 production by cultured normal hu man CD4+ T cells, (viii) down-regulation of tumor necrosis factor-alph a production by CD8+ T cells, and (it) inhibition of class LT major hi stocompatibility complex antigen expression on IFN-gamma-stimulated hu man monocytes. Another nonapeptide (IT9403) close to the NH2-terminal part of hIL-10 did not reveal cytokine synthesis inhibitory properties , but proved to be a regulator of mast cell proliferation, In conclusi on, we have identified two functional domains of IL-10 exerting differ ent IL-10 like activities, an observation that suggests that relativel y small segments of these signal proteins are responsible for particul ar biological functions.