RIFKIN, db: TGF-� activation; Normal and Pathological Consequence

The cytokine TGF-� is normally found in a latent from in the extra cellular milieu. Latent TGF-� consists of the mature cytokine dimer associated by non covalent interactions with its propeptides as well as a second gene product, the latent TGF-� binding protein (LTBP). In this state TGF-� is unable to interact with its high affinity receptor. Thus, the mechanisms of dissociating latent TGF-� from the latent complex are crucial in controlling the action of this important signaling molecule. A number of mechanisms have been described. These include extremes of pH, chaotropic agents, thrombospondin-1, the integrin aV�6, and proteases. I will describe the consequences of integrin activation as well as the results when the LTBPs are modified. In both cases profound effects are observed either on inflammation or on development. These results imply that these mechanisms of the controlled activation of the latent cytokine at the right place and/or time are crucial for proper function of the TGF-�s.