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Disturbed Th1/Th2 antagonism in male schizophrenic patients

Similar to the results in the whole group of healthy controls, all serum, whole blood assay, and lymphocyte Th1/Th2 ratios of control males showed clear antagonisms between IFN-γ and IL-4, IL-10, IL-13 according to the findings from multiple regression. That is, IFN-γ significantly positively correlated to IFN-γ/IL-4, IFN-γ/IL-10, and IFN-γ/IL-13 in healthy controls. In contrast, the major Th2 cytokines IL-4, IL-10, and IL-13 were markedly negatively associated with IFN-γ/IL-4, IFN-γ/IL-10, and IFN-γ/IL-13, correspondingly. However, the antagonism between whole blood assay IFN-γ/IL-4 and that between lymphocyte IFN-γ/IL-10 and IFN-γ/IL-13 were lacking in schizophrenic males. Male subjects with schizophrenia appeared to have a disturbed antagonistic mechanism between both T helper-systems in both in vitro systems.

Except cortisol, all parameters measured were involved in Th1/Th2 balance in male patients Even though both the whole schizophrenic group and the male schizophrenic subgroup had a disrupted Th1/Th2 antagonism, the results concerning the possible causes of Th2-shift from multiple regression in male schizophrenic subjects showed a different picture from that in the whole schizophrenic group. Except cortisol, all the other parameters measured in this study such as SHBG, age, prolactin, estradiol, testosterone, and IL-6 might be directly involved in

serum and whole blood assay Th1/Th2 imbalance in male schizophrenics, in addition to the key factors IFN-γ, IL-4, and IL-10. In addition, IL-2 and TNF-α likely played an indirect role in the Th1/Th2 balancing in schizophrenic men because they were significantly related to IFN-γ and IL-4, respectively.

Involvement of various endocrinological parameters in male schizophrenic patients

Male schizophrenics had in general lower serum cytokine levels, testosterone, SHBG, however, higher prolactin levels than control men. In contrast to the results from the whole group of schizophrenic patients, all hormones except cortisol measured in this study exerted effects on the Th1/Th2 ratios in males with schizophrenia according to the findings from multiple regression analysis.

Generally, Th2-shift in male schizophrenic patients was less explicit than that in their female schizophrenic counterparts. Males were found to show a higher Th1/Th2 ratio compared with females (Giron-Gonzalez et al., 2000). The reason might be that males had higher levels of testosterone than females since testosterone was shown to favor Th1-shift (Huber et al., 1999). However, testosterone was not the explanation for the diversity in Th1/Th2 ratios between both male subject groups in our study because male subjects with schizophrenia had markedly lower testosterone levels than male controls. Reduced testosterone levels in male schizophrenic patients might be the outcomes of noticeably elevated prolactin since injection of prolactin resulted in decreased testosterone (Romanowicz et al., 2004). Various factors could have effects on prolactin; they include neuroleptic medication, cortisol, TNF-α, and IFN-γ (Hyde et al., 2004; Wallaschofski et al., 2003; Walton and Cronin, 1990). Higher prolactin in male schizophrenics probably was a result of neuroleptic medication. But it was unlikely an outcome of changes in cortisol, TNF-α, and IFN-γ, because male schizophrenic patients and controls had comparable levels in those parameters.

Summarized findings from multi-variance and multiple regression analysis in male patients Schizophrenic men as a whole group had neither markedly higher serum IL-4 nor noticeably lower serum IFN-γ than male controls. The findings from multi-variance analysis in which IFN-γ and IL-4 were surveyed separately seemed to implicate that IFN-γ and IL-4 did not antagonize each other in male schizophrenics. Multi-variance analysis is applied to compare the differences in diverse variables between or among various groups. The outcomes from multi-variance analysis only suggested no marked diversity in IFN-γ, IL-4, and IFN-γ/IL-4 ratio between both male diagnostic subgroups. However, the findings from multiple regression of serum Th1/Th2 ratios revealed that IFN-γ correlated tremendously positively,

while IL-4 and IL-10 associated extremely negatively with IFN-γ/IL-4 and IFN-γ/IL-10 in schizophrenic men. That is, those male schizophrenics who had lower serum IFN-γ also had higher serum IL-4 and IL-10 and vice versa. Compared to female subjects with schizophrenia, male schizophrenic patients had less marked reductions in both serum IFN-γ/IL-4 and IFN-

γ/IL-10 ratios. The reason could be that males had higher levels of testosterone than females since testosterone was shown to favor Th1-shift (Lambert et al., 2004; Burger and Dayer, 2002). Reduced testosterone levels in male schizophrenic patients could, therefore, have contributed to the less pronounced reductions in both serum IFN-γ/IL-4 and IFN-γ/IL-10 ratios. The explanation for why the reduction in serum IFN-γ/IL-4 in male subjects with schizophrenia was less obvious than in female schizophrenics could be that IL-4 mRNA expression were found to be lower in males than in females; testosterone, at least in part, may be responsible for the decreased Th2 cell responses in males in vivo (Hayashi et al., 2003). Possible causes of Th2-shift in schizophrenic males

Further deficit(s) in the macrophage system in male schizophrenia?

Male schizophrenic patients had significantly reduced serum IFN-γ/IL-10, but not IFN-γ/IL-4 ratios if compared with healthy males. Deficits within the typical Th1/Th2 differentiation routes could be less explicit in schizophrenic males because IL-10 is not a typical Th2 cytokine. Th1/Th2 imbalance caused by deficits within the classical Th1/Th2 developmental pathways might have been compensated by testosterone since testosterone was found to favor Th1 development (Giltay et al., 2000). In addition, it could indicate further deficit(s) in other sites than the typical Th1/Th2 pathways. In humans, IL-10 is produced by activated CD8+ T cells, CD4+ T cells (Yssel et al., 1992), macrophages/monocytes, and mast cells (Verreck et al., 2004; Haddad et al., 2003). Reduced serum IFN-γ/IL-10, but not in whole blood assay IFN-γ/IL-10, could suggest that the sources of imbalance in serum IFN-γ/IL-10 lie at least partially in the factors which were excluded in the stimulated whole blood system. The candidate factors could be macrophages or mast cells since both cell types were not or less likely found in whole blood. Macrophages were more likely than mast cells as another possible sites of deficit in male subjects with schizophrenia because macrophages produce both IFN-γ and IL-10, but not IL-4 (Yanagawa et al., 1999; Havell and Spitalny, 1983). Over- activation in the macrophage/monocytes system could happen in male subjects with schizophrenia. Abnormality in macrophages was actually already observed in schizophrenia over 2 decades ago (Livni et al., 1979). Possible pathogenic mechanisms behind lymphocyte activation and macrophage dominance were once considered as the causes of acute psychotic symptoms (Nikkila et al., 2001). The macrophage-T-lymphocyte theory was ever postulated

as a possible etiological mechanism in schizophrenia (Smith and Maes, 1995). Accordingly, chronically activated macrophages and T-lymphocytes were previously proposed as the fundamental mediators of schizophrenia. Over-activation of macrophages could have led to over-production of IL-12 and IL-10. Additionally, a consistent hyper-production of IL-12 could again result in persistently elevated IL-10 and reduced IFN-γ, TNF-α, and IL-6 levels (Portielje et al., 2003).

Hormones: prolactin, SHBG/testosterone

Further factors such as prolactin and SHBG/testosterone could have partly contributed to Th1/Th2 imbalance in male schizophrenics since both male subgroups were remarkably different in those variables. They were elucidated in the previous section “7.4.1.The whole group of schizophrenic patients”. The male schizophrenics of this study had evidently “accelerated aging” regarding their testosterone levels. Their testosterone levels were much lower than those in male controls, despite that both male subgroups were of similar ages. Our male patients had only about 2/3 of the average control testosterone level. The reduction ratio in testosterone of our male schizophrenics was similar to that of normal men at the age of 70 yrs (Vermeulen, 2003). Decreased testosterone levels in male people with schizophrenia may be caused by significantly elevated prolactin as prolactin injection led to reduction in testosterone (Romanowicz et al., 2004). The roles of gonadal steroids such as testosterone in neurite outgrowth, cell differentiation, cell death, synaptogenesis, and the determination of cell position in earlier developmental phases were reported over one decade ago (Tobet et al., 1994). Neuronal loss was prevented by simultaneous administration of testosterone in vivo and in vitro (Mizoguchi et al., 1992). Progressive and long-term sex hormone imbalance was found to lead to degenerative changes in the CNS (Danilovich et al., 2003). Markedly reduced testosterone and SHBG could hint at a neurodegenerative process occurring in one subgroup of male schizophrenic patients. In addition, they implicate possible cognitive dysfunctions in schizophrenic males since they were shown to be linked to cognitive function in Alzheimer’s disease (Hoskin et al., 2004; Hogervorst et al., 2003). Moreover, reduced testosterone and SHBG likely explained why the Th1/Th2 ratios were less overt in male schizophrenics than in their female schizophrenic counterparts because testosterone is thought to shift the development of T-helper cells towards Th1 (Huber et al., 1999). Although elevated serum prolactin concentrations often correlate with abnormalities in immune responses (Brand et al., 2004), increased prolactin levels in male schizophrenic patients were probably raised by neuroleptic medication (Meaney et al., 2004). Prolactin was found to trigger the production of Th1 cytokines like IFN-γ, IL-12 and TNF-α, but not Th2 cytokines such as IL-6 and IL-10

(Carreno et al., 2004; Rovensky et al., 1999). Less clear Th2-shift in male people with schizophrenia could be ascribed to the elevation in prolactin levels.

Those endocrinological parameters might have direct or indirect impacts on Th1/Th2 balance. Nevertheless, they were not the only causes. Serum Th2-shift defined as significantly reduced IFN-γ/IL-10 ratio in schizophrenic males remained clear after the effects of those hormones mentioned above were controlled.