MONOCYTE INDUCTION OF IL-10 AND DOWN-REGULATION OF IL-12 BY IC3B DEPOSITED IN ULTRAVIOLET-EXPOSED HUMAN SKIN

CD11b(+) monocytic/macrophagic cells (Mo/Mph), which infiltrate into s kin after UV irradiation, play an important role in UV-induced immunos uppression, Because in mice, blockade of CD11b (iC3b receptor) on mono cytes and depletion of its ligand, iC3b, reverses UV-induced immunosup pression, we asked whether iC3b is deposited in human skin after UV, a nd whether iC3b can modulate the cytokine profile of Mo/Mph, Immunoflu orescence studies revealed that iC3b was newly deposited in UV-exposed skin and was localized in apposition to infiltrating CD11b(+) Mo/Mph. In addition, in situ hybridization studies showed that TNF-alpha mRNA was also induced in a similar microanatomic localization. To model th e effects of these complex signals on infiltrating Mo/Mph following UV exposure, we then tested the effects of immobilized iC3b and TNF-alph a on resting blood monocytes, Both IL-10 mRNA synthesis and protein se cretion were significantly induced by binding of iC3b in vitro and wer e synergistically increased by the presence of TNF-alpha. The effect w as abrogated by a blocking Ab to CD11b, indicating CD11b-iC3b interact ion. In contrast, iC3b binding resulted in suppression of IL-12 p40 mR NA and significantly inhibited the production of IL-12 p70 protein. Ou r studies thus define a novel mechanism for induction of tissue Mo/Mph into an IL-10(high)/IL-12(low) state via iC3b in combination with TNF -alpha.