A hypothesis resolving the apparently disparate activities of native and altered forms of human C-reactive protein

Although C-reactive protein (CRP) has been studied for over 60 years, the in vivo function of this acute-phase reactant has not been clearly defined. The literature on CRP has been divided here into three categories: the cyclic, pentameric blood-borne form of CRP termed 'native' CRP which has activities mainly associated with the resolution of inflammation, conformationally altered and aggregated forms of CRP which display pro-inflammatory properties, and proteolytic forms of CRP exhibiting mixed activities. Since the activities of certain forms of CRP in some cases contradict others, a hypothesis has been developed which reconciles these differences. It is proposed that distinct species of CRP are formed which have unique activities at an inflammatory site; conformationally altered and proteolytic forms of CRP are created in succession from bound native CRP at the inflammatory site due to local conditions (e.g. lowered pH, oxygen radicals, or possibly enzymes). Aggregated and/or conformationally altered forms of CRP initially promote inflammation, and subsequently produced peptide products either up or down regulate different leukocyte activities to aid in the progression of the inflammatory event. As the local conditions favoring the conversion of native CRP to altered forms begin to subside, native CRP then predominates at the site, facilitating the removal of cellular debris and resolution of the lesion.