As 106 cells secrete 50�C100ng PTX3, and 106 cells occupy approximately 100 mm3 this suggests that the local concentration of PTX3 within tissues could reach 1��g/ml, and be even higher within the lung interstitium. Surface plasmon resonance experiments show that SAP and CRP, bind to all of the human Fc��R, whereas PTX3 only binds to human Fc��RIII and weakly to human Fc��RIIA. However, we observed that PTX3 binds to Fc��RI and Fc��RIIA on leukocytes, K562 cells, and transfected HEK293 cells. This inconsistency with the previously published data maybe explained by the differences in the glycosylation state of the receptors and/or the lack of some intracellular RGD signaling components that promote receptor binding. As Fc��RI and Fc��RIIIA lack an intrinsic motif that binds to intracellular signaling components, they interact with the intracellular protein FcR��. The absence of FcR�� reduces the affinity of Fc��RI and Fc��RIIIA for IgG in humans. This can potentially alter PTX3 binding to Fc��RI and Fc��RIIA. Together, this suggests that the PTX3 affinity for Fc��Rs is dependent on the modification of these Fc��Rs and the interactions they make before binding PTX3. There are several possible explanations for the observation that SAP appears to signal through Fc��RI on monocytes to inhibit fibrocyte GW2580 differentiation, while PTX3 appears to signal through the same receptor on the same cells to promote fibrocyte differentiation. At first glance, it would appear that SAP might be an agonist, andPTX3 an inverse agonist of Fc��RI, but the observation that in serum-freemedium, mouse cells lacking Fc��RI show only slightly reduced levels of fibrocyte differentiation, suggests that there is little constitutive signaling from Fc��RI with respect to promoting or inhibiting fibrocyte differentiation. In humans, the main activating Fc��Ron monocytes are Fc��RI, Fc��RIIA, and Fc��RIIIA, whereas in mice the main activating Fc��Ron monocytes are Fc��RI, Fc��RIII, and Fc��RIV. Human Fc��RI is orthologous to mouse Fc��RI, human Fc��RIIA is most closely related to mouse Fc��RIII, and human Fc��RIIIA is most closely related to mouse Fc��RIV.