Informe Anual del Potencial Hidrocarburífero del Ecuador 2017 (Documento

T G F -p belongs to a su perfamily of growth factors c o m p r is i n g three m am m ali an isofor ms (TGF-p 1-3) activ in s/i nhi bi ns and bon e m o r ph o ge ni c

proteins. 80% sequence homology exists between the three TG F-p isoforms, the b io lo gi cal functions of each being very similar. The major differ enc e lies in the potency of the variants, in that TGF -P 1 and 3 are

ef fective at co n cen tr ati o ns up to 100-fold lower than T G F - p i (Mas sague,

1990; Staunezer, 1995). T G F - p l has been used t h ro u gh o u t the studies des cri bed in this chapter.

T G F -p is inh ib it ory to virtually all immune and ha em o po ie ti c fu nct ion s. It is p r o d uc ed by mac ro pha ges , DC, platelets and a lim it ed nu m be r of lymphocytes (Mas sague, 1990; Sn apper et al, 1987; Staun eze r, 1995). TGF- p inhibits the im m une function and pro lifer atio n of all ly m pho cty es and myeloid lineage deri ved cells (Dubois et al, 1990; Massa gu e, 1990; Panek

et al, 1995). Its i m p o rta nc e in such a role is clearly d e m o n st r a t e d by the TG F -p kn ock out m ouse model. Such animals die of an ex ten siv e, exce ssi ve in fla m m at or y re sponse within 3 - 4 weeks of birth (Geiser et al, 1993).

TG F -p plays an im po rta nt role in plasm a cell d if f er en ti at io n in that it is re sp o n s ib le for indu cin g the class switching that leads to IgA f orm ati on (Massa gu e, 1990; Staunezer, 1995). This occurs in the P e y e r ’s patch es of the ga s tro in te st in al epit hel iu m, in which mucosal B cells are e x p o s ed to

T G F - p prior to termi nal differentiation. Such cells leave the P e y e r ’s patch via the mes en te ric lymph node and thoracic duct and will home b ac k to the l a m in a pro pri a of the gut and to other mucosal sites where sIgA will be re le as ed to cross the mucosal epi the li um to form a d ef en civ e h um ou ra l layer (S taunezer, 1995). IL-6 interacts with TG F -p at this stage in that it is

r eq ui red to pr om o te the post-class switch secretion of IgA antibody. TG F-p is also re sp o ns ib le for class sw itching to I g 0 2 b pr odu cin g p la sm a cells (Sta une zer , 1995)

The m ec h a n i s m respon si ble for the TGF-P media ted in hib ition of immune cell p r ol i f er at i on , is an arrest of the cell cycle in the G1 phase (Dubois et al, 1990; M assague, 1990; Gray et al, 1994; Ma & N i ede rk orn , 1995; Panek

et al, 1995). TG F -p in fact, controls cell di v isi o n / p r o l i fe r at i o n through an in di re c t reg ul atio n of bcl-2 expression. In reg ul at ing bcl-2 ex pr ess io n, TGF-P will act to control rates of F A S - m e d ia t ed B cell ap op to sis (Lomo et

al, 1995). The in hibition of cell cycle medi ated by T G F -p is rev ers ible, but is also dose dependent. As with high exogen ou s IL-6 levels, high doses of T G F -p can cause terminal di ffe re nti ati on and eventu al apo ptosis. In a p h y s io lo g ic al context, TG F-p driven apoptosis may play a role in the r emoval of self -re ac tiv e im mature B cells or u ns ele cte d sec ond ary phase B cells in germinal centres of lymphoid follicles. M atu r at io n and p r ol if er at io n of both pre-B cells and thymocytes is inh ibited by TG F-p .

T ak en t og et h er with the ability of TG F -p to pr omo te c la s s- sw it ch in g, TGF- P appears to exert a num ber of tight re gu latory con trols on the B l y m pho cyt e popu lation .

T G F - p ’s inh ibito ry effects on ha em op o ies is are media ted throu gh an i nh ib i t i o n of IL-1, IL-3 and CSF induced d ev elo pm en t of p r e c u rs o r cells (Du bo is et al 1990). TG F-p is known to do w nr egu lat e both IL-1 and IL-2 r ec ep to r ex p re ss io n on T and B lymphocytes (Dubois et al, 1990; Rei m ol d

et al, 1993; Pan ek et al, 1995). This may well play a central role in the i n h i b i t i o n of im m un e function of lymphocytes and other i m m un e cells f o ll o w in g T G F -p treatment.