Extrahepatic synthesis of complement proteins in inflammation

The demonstration of local complement protein synthesis leads to speculation as to the biological significance of this phenomenon. A narrative review is provided to illuminate several queries. It is difficult to establish a causal role for the locally produced complement because participation of systemic complement cannot be excluded. It is also difficult to discern whether local complement synthesis is a beneficial response to an inflammatory event or whether it promotes tissue damage. Finally, it remains to be seen if the roles of local and systemic complement differ in these respects. Extrahepatic expression of complement components of the activation pathways may provide a rapid response to microbial invasion. Once produced and activated, these proteins evoke a phlogistic response composed of cells and soluble mediators of inflammation. Many cells, not only synthesize complement proteins, but can also be stimulated via their complement receptors. This positive feedback may enhance local immune defense, especially in organs isolated from plasma components. In addition, local environmental factors in different organs may differentially regulate complement synthesis. These factors may include pro-inflammatory molecules and non-immune effectors, such as tissue ischemia/reoxygenation and drugs. Local complement dysregulation due to inhibition of activity of a complement regulatory component was shown to cause disease and restoration of the capacity to regulate the complement pathway restored health. Extrahepatic complement synthesis may also modulate local cellular responses, as to decrease detrimental damage of the inflammatory reaction. The demonstration that complement proteins play a significant role in the clearance of apoptotic cells suggests that local synthesis and activation of complement may contribute not only to tissue damage but also to tissue repair.