HYPOTHESIS: AN ALTERNATIVE PATHWAY FOR THE REGULATION OF INFLAMMATION

Regulation of inflammation is a crucial event since its alteration, such as in sepsis and chronic autoimmune (i.e. rheumatoid arthritis, lupus erythematosus) or infectious diseases (i.e. tuberculo- sis, leprosy), determines severe tissue damage. Although there is a general consensus that regulation of in- flammation results from a balance between proinflammatory and antiinflammatory pathways, we arrived at the conclusion that well known chemoattractants/proinflammatory molecules such as bacterial formyl peptides or immune complexes (IC), could induce, paradoxically, strong antiinflammatory effects. Thus, we demonstrated that N-formyl-methionyl-leucyl-phenylalanine (FMLP) exerted a drastic antiinflammatory effect, inhibiting the se- cretion of tumor necrosis alpha (TNF-α ) induced by lipopolysaccharides, a potent TNF-α inducer. We also de- termined that in human neutrophils FMLP and IC induced the downregulation of receptors for the Fc portion of IgG (FcγRII and FcγRIIIB). Moreover, FMLP inhibited interferon gamma (IFN-γ)-induced FcγRI expression and IC downregulate class II molecules of the major histocompatibility complex on monocytes. Part of these effects were mediated by the release of aspartic-, serin-, or metalloproteases. All these results favor the postulation of a new concept on the regulation of inflammation carried out through an alternative and non conventional path- way, in which a chemoattractant/proinflammatory agent could, under certain circumstances, act as an antiinflammatory molecule.