The Rollins laboratory works on chemokines, which are low molecular weight proteins that attract specific leukocyte subtypes. Because there are over 50 chemokines and 20 chemokine receptors, the approach we have taken to understanding these proteins is to study one chemokine in great depth. This is Monocyte Chemoattractant Protein -1, or MCP-1, a CC chemokine that specifically attracts monocytes, memory T cells, and NK cells in vitro. We have attacked the MCP-1 problem at multiple levels. First, we have performed structure/activity analyses that define regions of MCP-1 that are essential for its chemoattractant activity.
In the course of this work, we identified potent antagonists of MCP-1 that we are developing into reagents for in vivo use. Meanwhile, our in vitro work continues with an interst in detemining whether or not MCP-1 activates its receptor, CCR2, as a dimer (as the solved structure of MCP-1 would indicate), and whether or not that imples receptor dimerization, which would be somewhat heretical for a G protein-coupled, seven transmembrane spanning receptor. To complement our in vitro work, we have examined MCP-1's function in vivo using several genetically modified mouse models. Because of questions about MCP-1's specificity in vivo, we constructed a transgenic model in which MCP-1 expression is localized to pancreatic islets. These mice have pronounced monocytic islet infiltrates, but do not develop diabetes, indicating that in some settings, chemokines are designed to attract cells without activating them. We have now constructed conditional transgenics (i.e. tetracycline-inducible) to ask questions about monocyte emigration from inflammatory sites. Because of the large number of chemokines that attract monocytes, many in the field have been concerned that there is inherent redundancy in the chemokine system.
To address this issue, we constructed an MCP-1 deficient mouse by targeted gene disruption. Despite the existence of other monocyte-active chemokines, this mouse cannot attract monocytes in several inflammatory models, indicating an essential and non-redundant role for MCP-1. We demonstrated similar specificity in disease models. For example, even when severly hypercholesterolemic, MCP-1 deficient mice are protected from atherosclerosis. We are now developing cancer models to determine whether or not MCP-1 also plays a role in tumor suppression. Most recently, we have discoverd that MCP-1 deficient mice are incapable of mounting a Th2 response, even though their Th1 responses are intact. This appears to occur buy means of cells in secondary lymphoid organs that constitutively secrete MCP-1. Thus, in addition to its role in inflammatory settings, MCP-1 appears to have an influence on shaping T helper responses, suggesting that chemokines involved in innate immunity also have an impact in acquired immunity. We are now using chip array technology to examine gene expression patterns induced by MCP-1 in this setting.
Finally, we have begun to branch out in our chemokine work. We have biochemically documented the existence of a novel receptor for the CXC chemokine IP-10, and find that its distribution includes non-leukocytic cells. In the future, we will continue to pursue chemokine effects that extend beyond leukocytes and, in particular, we will focus on chemokines and epithelial cells.
Ren S, Rollins BJ. Cyclin C/cdk3 promotes Rb-dependent G0 exit. Cell 2004 Apr 16; 117(2):239-51
Panoskaltsis-Mortari A, Hermanson JR, Taras E, Wangensteen OD, Charo IF, Rollins BJ, Blazar BR. Post-BMT lung injury occurs independently of the expression of CCL2 or its receptor, CCR2, on host cells. Am J Physiol Lung Cell Mol Physiol 2004 Feb; 286(2):L284-92
Kleine-Lowinski K, Rheinwald JG, Fichorova RN, Anderson DJ, Basile J, Münger K, Daly CM, Rösl F, Rollins BJ. Selective suppression of monocyte chemoattractant protein-1 expression by human papillomavirus E6 and E7 oncoproteins in human cervical epithelial and epidermal cells. Int J Cancer 2003 Nov 10; 107(3):407-15
Soejima K, Rollins BJ. A functional IFN-gamma-inducible protein-10/CXCL10-specific receptor expressed by epithelial and endothelial cells that is neither CXCR3 nor glycosaminoglycan. J Immunol 2001 Dec 1; 167(11):6576-8
Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol 2001 Feb; 2(2):108-15
Last Update: 1/6/2014