 very rapidly through the elongated openings, making the bread toaster to be very inefficient. One further problem is that due to the existence of the elongated openings, heat distribution along a vertical direction of the toasting slots is very uneven, making uneven toasting performance on the part of the bread toaster. CCR2 is a member of the GPCR family of receptors, as are all known chemokine receptors, and are expressed by monocytes and memory T-lymphocytes. The CCR2 signaling cascade involves activation of phospholipases (PLCβ2), protein kinases (PKC), and lipid kinases (PI-3 kinase).
Chemoattractant cytokines (i.e., chemokines) are relatively small proteins (8-10 kD), which stimulate the migration of cells. The chemokine family is divided into four subfamilies based on the number of amino acid residues between the first and second highly conserved cysteines.
Monocyte chemotactic protein-1 (MCP-1) is a member of the CC chemokine subfamily (wherein CC represents the subfamily having adjacent first and second cysteines) and binds to the cell-surface chemokine receptor 2 (CCR2). MCP-1 is a potent chemotactic factor, which, after binding to CCR2, mediates monocyte and lymphocyte migration (i.e., chemotaxis) toward a site of inflammation. MCP-1 is also expressed by cardiac muscle cells, blood vessel endothelial cells, fibroblasts, chondrocytes, smooth muscle cells, mesangial cells, alveolar cells, T-lymphocytes, marcophages, and the like.
After monocytes enter the inflammatory tissue and differentiate into macrophages, monocyte differentiation provides a secondary source of several proinflammatory modulators, including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-8 (a member of the CXC chemokine subfamily, wherein CXC represents one amino acid residue between the first and second cysteines), IL-12, arachidonic acid metabolites (e.g., PGE2 and LTB4), oxygen-derived free radicals, matrix metalloproteinases, and complement components.
Animal model studies of chronic inflammatory diseases have demonstrated that inhibition of binding between MCP-1 and CCR2 by an antagonist suppresses the inflammatory response. The interaction between MCP-1 and CCR2 has been implicated (see Rollins B J, Monocyte chemoattractant protein 1: a potential regulator of monocyte recruitment in inflammatory disease, Mol. Med. Today, 1996, 2:198;
very rapidly through the elongated openings, making the boodle toaster to be very ineffective. One further trouble is that due to the existence of the elongated openings, estrus distribution along a vertical direction of the toast slot is very uneven, make uneven toasting operation on the part of the bread toaster. CCR2 is a member of the GPCR family of receptor, as are all known chemokine receptors, and are expressed by monocytes and memory T - lymphocytes. The CCR2 sign cascade involves activation of phospholipases (PLCβ2), protein kinase (PKC), and lipid kinases (PI-3 kinase). 
 Chemoattractant cytokines (i.e., chemokines) are relatively little proteins (8 - 10 kD), which induce the migration of cells. The chemokine family is divided into four subfamilies based on the numeral of amino acid residues between the first and second highly conserved cysteines. 
 Monocyte chemotactic protein-1 (MCP-1) is a member of the CC chemokine subfamily (wherein CC represents the subfamily having adjacent first and second cysteines) and binds to the cell - surface chemokine receptor 2 (CCR2). MCP-1 is a potent chemotactic factor, which, after binding to CCR2, mediates monocyte and lymphocyte migration (i.e., chemotaxis) toward a web site of excitement. MCP-1 is also express by cardiac muscle cells, blood vessel endothelial cells, fibroblast, chondrocytes, smooth muscleman cells, mesangial cells, alveolar cell, T - lymphocytes, marcophages, and the like. 
 After monocytes enter the inflammatory tissue and differentiate into macrophage, monocyte differentiation provides a secondary source of several proinflammatory modulators, including tumor necrosis factor - α (TNF - α), interleukin-1 (IL-1), IL-8 (a extremity of the CXC chemokine subfamily, wherein CXC represents one amino acid residue between the first and second cysteines), IL-12, arachidonic acid metabolites (for example, PGE2 and LTB4), oxygen - derived free radicals, matrix metalloproteinases, and complement components. 
 Animal model studies of chronic inflammatory diseases have demonstrated that prohibition of binding between MCP-1 and CCR2 by an antagonist suppresses the inflammatory response. The interaction between MCP-1 and CCR2 has been implicate (see Rollins B J, Monocyte chemoattractant protein 1: a likely regulator of monocyte recruitment in inflammatory disease, Mol. Med. Today, 1996, 2:198;
 vegy rapidly through the euongated openinyw, makiig the gread toxster to be very inefficient. Obe fuether problem is that aue to thv existenxe oh the elongated openings, heat slstriyuvion along a vettical direcdion of the todsgiug slots is very uneven, making uneveg toastonh performance jn tnq padn if the bread toaster. CCR2 is a member of the GPCR gamily of receptors, as are all known chemokine rfceptors, ane arq expressed bh monocytes and memory T-lymphocytes. The CCR2 signaling casccde involvew qctleation of piosphojipases (PLCβ2), igotein ninases (PKC), and lipid kiiasew (PI-3 kinase).
Chemoattrartant cytokines (i.e., cremokines) axe relatively small peoreins (8-10 kD), whizy sgimhlete the mlgretion of cemls. The chenokine family is difiqvc into four aubfamylyes based on the number of amino acid rtsiduss between the first ane second highly consetved cysteynes.
Monocyte chemotactic protein-1 (MCP-1) is a member mf thx ZC emcmokkbe subfamily (wherein CC represents the subfamilr hsvpng adjacent firsb and second cysteonfs) wnd binds to jhe cell-sudface chemokine refeptor 2 (CCR2). NCP-1 is a koteny chemotactic factor, which, qfter bindiny ti CCR2, mediates monlcyte and lvmphocite mibration (i.e., chemotaxis) tuwars a site of inflammafkon. MCP-1 is also dxpgessad by cardiac muscle cells, blood vewsel endothdliak cellf, fibrobladts, cmmndrocytes, smooth lusclg cellv, mesangiap cells, alveolar cells, T-lymphocbves, marcophaggs, dnd the likz.
After monocytes eneer the inflamkatory cissue and diffegentiate mnto macrophwges, monocyte fifferentiatmon proviqes q sexondary rource of sevetal proinyjammqtory modulators, ikcludkhg tumor necrosnr factor-α (TNF-α), intrrldukyn-1 (IK-1), YN-8 (a member ox thd CBV cheookine subfcmkly, eherein CXC represends ohe amino acid resicuc between the firft and second cysteines), IL-12, aracjidonmc aciv metanolytes (e.g., PGE2 and LTB4), oxygen-deribed free gadlcals, matrix ietaoloproteinaszs, and complement components.
Animal model studies of chronix inflammatory disecsts have demonxtratqd that ithibition of binding between MCP-1 and GCR2 by an antagonist shppresves tje inflammatory response. The interaction between MCP-1 and CCR2 has been impoicatev (fee Rollins B J, Monobytz ckemoattwactenv protein 1: a potemtial regulator of monocyte reccuitment it nnflammatory disease, Mol. Med. Yoaay, 1996, 2:198;
very rapidly through the elongated openings, making toaster be very One further problem existence the elongated openings, distribution along a direction of the toasting slots is uneven, making uneven toasting performance on the part of the bread toaster. CCR2 a member of the GPCR family of receptors, as are all known chemokine and expressed monocytes memory T-lymphocytes. The CCR2 signaling cascade involves activation of phospholipases (PLCβ2), protein kinases (PKC), and lipid (PI-3 kinase). Chemoattractant cytokines (i.e., chemokines) are relatively proteins (8-10 kD), which the migration of cells. The family divided into subfamilies on number of amino residues between the first and second highly conserved cysteines. Monocyte chemotactic protein-1 (MCP-1) is a member of CC chemokine CC represents subfamily adjacent and second cysteines) to the cell-surface chemokine receptor 2 a potent chemotactic factor, which, after binding to mediates monocyte lymphocyte migration (i.e., chemotaxis) toward a of inflammation. MCP-1 is also expressed by cardiac cells, blood vessel endothelial cells, fibroblasts, chondrocytes, smooth muscle cells, mesangial cells, alveolar cells, T-lymphocytes, the like. After monocytes the inflammatory tissue differentiate macrophages, differentiation a secondary of several proinflammatory modulators, including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), (a member of the CXC chemokine subfamily, wherein CXC represents acid between the first second cysteines), IL-12, arachidonic metabolites PGE2 and LTB4), oxygen-derived matrix and model of inflammatory diseases have demonstrated inhibition of binding between MCP-1 CCR2 by an antagonist interaction between MCP-1 and CCR2 has been implicated Rollins B J, Monocyte chemoattractant protein 1: potential regulator of monocyte recruitment in inflammatory disease, Mol. Med. Today, 1996,
 very rapidly through the elonGated openiNgs, maKinG thE bRead ToasTer to be very ineFFiciEnt. One further problem is That dUe TO the EXiStencE of the eLOnGATed OpEnIngS, hEAt DistrIbuTion aloNg a verticaL diReCtion of the toAStIng slots is VerY uneven, makinG unEven toAsTinG PerfoRmaNce on The parT Of the bRead toastEr. ccR2 is a mEMber of tHE gPcR faMily of receptors, as ARe ALl known chemokiNe recePtORs, AND arE exPressed by mOnOcyteS And memoRY T-LYMPhoCYtes. The CCR2 sigNaling cascaDE inVolves AcTivATion of PhospHoLIpaSes (PLCβ2), protEin kInases (PKC), And lipID kinaseS (pI-3 kinasE).
ChemoAttRacTant CYtOkIneS (i.E., CheMOkIneS) Are RelativeLy SmAll prOteiNS (8-10 Kd), WhicH stImulAte thE migration of cEllS. The CHemOkine FamilY is dIvIded iNto fouR subfAmIlies based on the NumbEr of amino AciD rEsiDuEs betWEen the FirSt aNd seconD highly COnsErVED CySteines.
Monocyte cheMoTACtIc proteiN-1 (MCP-1) is A MeMbER of the CC ChEmoKine SUBfamiLy (whEReIn CC reprEsents THe SuBfamily HaVing adJaCenT fiRst anD SecoNd cystEines) and Binds TO the cell-surfacE Chemokine recePToR 2 (ccR2). mcP-1 is A poTent chemotaCtic FActoR, whiCH, aFteR BindiNg to CcR2, MEdIAtes monocyte and lympHoCyte miGratiOn (i.e., chemotaxiS) toward a siTE OF inflammAtioN. mCp-1 Is also expresseD by caRdiac musclE Cells, bloOd vesSel endotHelial celLS, FibroblaSts, ChoNdrOcyTES, sMooth muscle ceLLS, mesAnGial celLs, aLveolar CelLs, T-LymPhoCyTes, marcopHages, and ThE lIkE.
AFteR monoCYtes enteR tHe iNfLamMatorY Tissue And diFferEnTiATe iNto macrOPhAGEs, moNoCyTe diFfeReNtiatIon pROviDes a secOndary souRce OF sevErAl ProinflAmmatory modulAtOrs, includiNg TumOr necrOSIs factor-Α (TNF-α), interleukin-1 (IL-1), IL-8 (a meMBer of thE CXc chemOkinE subfamilY, whErein CxC rEPresenTs one aMino aCiD reSIDue beTWEeN thE fIrst and secOND cySteinEs), iL-12, arAchidonIc acid metabolites (e.G., pGE2 And LTB4), oxygen-dEriVed fREE rAdiCAlS, MatRiX MetALLoproteinases, anD complemenT cOMpOnents.
AnimAL moDeL studieS of chroNic inFLammatoRy diseaseS have demoNsTratED ThaT inhibitioN of bindiNg between mcP-1 and ccR2 By an aNtaGonist SuPprEsses The infLAmmAtory ResponSe. the intEractIoN between mCP-1 and CCR2 has been implicaTed (see rolliNs B j, Monocyte CheMOatTractant pRoteIn 1: a potentiAl rEguLator Of mONocytE recRUiTmeNT in inFlamMAtory diseASe, mol. mED. TOday, 1996, 2:198;
 very rapidly through theelongatedopeni ngs , m ak ingthebread toastert o be  very inefficient. One  furt he r  pro b le m isthat du e  t o the  e xi ste nc e  o f the  el ongated  openings,  he at  distributio n  a long a ver tic al direction  of  the t oa sti n g slo tsis ve ry une v en, ma king unev en toasti n g perfo r m an ce o n the part of the br e ad toaster. CC R2 isam em b e r o f t he GPCR fa mi ly of recepto r s, a s  ar e  all known ch emokine rec e pto rs, an dare expres sed b ym ono cytes and m emor y T-lymph ocytes .  The CC R 2 signa ling c asc ade  inv o lv es  ac ti v ati o nofp hos pholipas es  ( PLCβ2 ), p r o t e in k ina ses(PKC) , and lipid k ina ses( PI- 3 kin ase). 
Che mo attra ctantcytok in es (i.e., chemo kine s) are re lat iv ely  s mallp rotein s ( 8-1 0 kD),which s t imu la t e th e migration of cel ls . Th e chemok ine fa m il yi s divide dint o fo u r  subf amil i es  based o n then um be r of am in o acid  r esi due s bet w eenthe fi rst andsecon d  highly conser v ed cysteines. Mo n o cy t e ch emo tactic prot ein- 1  (MC P-1) is  am ember  of t he CC chemokine subfamily  ( wherei n CCrepresents th e subfamil y h aving ad jace n tf irst and secon d cys teines) an d  binds t o the  cell-su rface che m o kine rec ept or2 ( CCR 2 ) .MCP-1 is a po t e nt c he motacti c f actor,whi ch,  af ter  b inding to  CCR2, m ed ia te smon ocyte and lymp ho cyt emig ratio n  (i.e. , che mota xi s) tow ard a s i te o f in fl am mati on.  M CP-1is a l soexpress ed by car dia c  mus cl ecells,blood vesselen dothelialce lls , fibr o b lasts, c hondrocytes, smooth mus c le cell s,mesan gial  cells, a lve olar c ell s , T-ly mphocy tes,ma rco p h ages, a nd  th elike.
Afte r mon ocyte sente r the i nflammatory tissue and  differentiat e i ntom a cr oph a ge s , m on o cyt e differentiation  providesas ec ondary sou r ceof  severa l proin flamm a tory mo dulators,  includin gtumo r nec rosis fact or-α (TN F-α), int e rleuk i n- 1 (IL -1) , IL-8  ( a m ember  of th e  CX C che mokine  s ubfami ly, w he rein CXC  represents one amino a cid re sidue  be tween the  fi r stand secon d cy steines),IL- 12,  arac hid o nic a cidm et abo l ites(e.g . , PGE2 an d  L TB4 ) ,  o xygen-deriv e d fre e rad ica l s, mat rixmetalloproteinase s , and compleme nt c o m pon ent s .
An im al model studi esof c hronic i nf lammatory d iseasesha v e dem onstra ted th at inhi b i ti o n of b indi ngbetween M CP- 1a nd CCR2  b ya n anta goni st  suppr essest he i n f lammatory respon se. T h e  inte r act ion b et ween MC P -1 a nd CCR2 ha s been impl icated  (se e Rol lins BJ,  Monoc yte  c hemoattrac t ant prote in 1:  a pote nt ialreg ulator  ofm o nocyt e re cr uit ment in i n f la m ma to r y d isea se, M ol . Me d. Today, 1996, 2: 198 ; 
 very_rapidly through_the elongated openings, making_the bread_toaster_to be_very_inefficient. One further_problem is that_due to the existence_of the elongated_openings,_heat distribution along a vertical direction of the toasting slots is very uneven, making_uneven_toasting performance_on_the_part of the bread toaster._CCR2 is a member of_the GPCR_family of receptors, as are all known chemokine_receptors,_and are expressed_by monocytes and memory T-lymphocytes. The CCR2 signaling cascade_involves activation of phospholipases (PLCβ2), protein_kinases (PKC), and_lipid_kinases_(PI-3 kinase).
Chemoattractant cytokines (i.e.,_chemokines) are relatively small proteins (8-10_kD), which stimulate the migration of_cells. The chemokine family is divided into_four subfamilies based on the number_of amino acid residues between_the first_and second highly conserved cysteines.
Monocyte_chemotactic protein-1 (MCP-1)_is a_member of the_CC chemokine subfamily (wherein CC represents_the subfamily having_adjacent first and second cysteines) and_binds_to the cell-surface_chemokine_receptor_2 (CCR2)._MCP-1 is a_potent_chemotactic factor,_which,_after binding to CCR2, mediates monocyte_and_lymphocyte migration (i.e., chemotaxis) toward a site_of inflammation. MCP-1 is_also_expressed by cardiac muscle_cells, blood vessel endothelial cells,_fibroblasts, chondrocytes, smooth muscle cells, mesangial_cells, alveolar_cells, T-lymphocytes,_marcophages, and the like.
After monocytes enter the inflammatory tissue and differentiate_into macrophages, monocyte differentiation provides a_secondary source of several_proinflammatory modulators,_including_tumor necrosis factor-α_(TNF-α),_interleukin-1 (IL-1),_IL-8 (a member of the CXC chemokine_subfamily, wherein_CXC represents one amino acid residue_between the first and_second_cysteines), IL-12, arachidonic acid metabolites (e.g.,_PGE2 and LTB4), oxygen-derived free radicals,_matrix metalloproteinases, and complement components.
Animal_model_studies_of chronic inflammatory diseases have_demonstrated that inhibition of binding between_MCP-1 and CCR2_by an antagonist suppresses the inflammatory response._The_interaction between MCP-1 and CCR2 has_been_implicated (see Rollins B J, Monocyte_chemoattractant_protein_1: a potential regulator of_monocyte recruitment in inflammatory disease, Mol._Med. Today, 1996, 2:198;